+publisher:"University of Houston" +contributor:("Frigo, Daniel E.")

University of Houston

1. -6543-5086. Regulation of Nutrient Uptake in Prostate Cancer.

Degree: PhD, Cell and Molecular Biology, 2017, University of Houston

► Prostate cancer is a hormone-driven malignancy that relies on the function of the androgen receptor (AR). AR is a transcription factor that regulates the expression… (more)

▼ Prostate cancer is a hormone-driven malignancy that relies on the function of the androgen receptor (AR). AR is a transcription factor that regulates the expression of many downstream targets, some of which can facilitate an important hallmark of cancer; metabolic reprogramming. Metabolic reprogramming allows the cancer to maintain an aberrant metabolism that supports uncontrolled cellular growth and survival. This reprogramming if often initiated by signaling pathways essential for growth and survival. There are therapies available that target AR signaling but they inevitably fail. Therefore, I sought to identify new potential targets that are downstream of AR and other oncogenic signals in prostate cancer and define the mechanism through which they are regulated. First, I investigated how two glutamine transporters, SLC1A4 and SLC1A5 (Solute Carrier Family 1A, members 4 and 5) were regulated in glutamine-addicted prostate cancer cells. I found that the transporters were hormone-responsive but not direct targets of AR. Downstream of AR they are regulated via mammalian target of rapamycin (mTOR) signaling and selectively regulated via MYC. Importantly I determined that SLC1A4 and SLC1A5 represented a central node of several oncogenic signaling pathways that controlled overall cell growth, making them promising targets for prostate cancer therapy. Next, I investigated the regulation of glucose uptake through SLC2A12 (GLUT12 (glucose transporter 12)). I found that SLC2A12 is a direct target of AR and is required for prostate cancer cell growth. GLUT12 is also regulated through calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-5’-AMP-activated protein kinase (AMPK) signaling. CaMKK2-AMPK activity promotes GLUT12 translocation to the plasma membrane via modulation of TBC1D4 (TBC1 Domain Family Member 4) and also regulation of TBC1D4 expression. Taken together my findings demonstrate that SLC1A4, SLC1A5, and SLC2A12 all have the potential to be prostate cancer therapeutic targets due to their modulation by major oncogenic signaling pathways and their functional role in cancer cell growth. Their essential role in cancer cell growth and easily accessible location on the cell surface suggest these proteins may be readily druggable. Thus, my findings highlight the utility of targeting pathogenic metabolism as a therapy and provide potential starting points for future translational research. Advisors/Committee Members: Frigo, Daniel E. (advisor), Zhang, Xiaoliu Shaun (committee member), Lin, Chin-Yo (committee member), Gilbertson, Scott R. (committee member), Coarfa, Cristian (committee member).

Subjects/Keywords: Glutamine; Glucose metabolism; Prostate cancer; MYC; MTOR; SLC1A4; SLC1A5; AMPK; CaMKK2; SLC2A12; GLUT12; TBC1D4

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APA (6^th Edition):

-6543-5086. (2017). Regulation of Nutrient Uptake in Prostate Cancer. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/4533

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Chicago Manual of Style (16^th Edition):

-6543-5086. “Regulation of Nutrient Uptake in Prostate Cancer.” 2017. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/4533.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

MLA Handbook (7^th Edition):

-6543-5086. “Regulation of Nutrient Uptake in Prostate Cancer.” 2017. Web. 16 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Vancouver:

-6543-5086. Regulation of Nutrient Uptake in Prostate Cancer. [Internet] [Doctoral dissertation]. University of Houston; 2017. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/4533.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Council of Science Editors:

-6543-5086. Regulation of Nutrient Uptake in Prostate Cancer. [Doctoral Dissertation]. University of Houston; 2017. Available from: http://hdl.handle.net/10657/4533

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

University of Houston

2. Wang, Jun 1988-. The Mechanisms of Tumor-suppressive miRNAs in Mammary Stem Cell Development and Triple-negative Breast Cancer.

Degree: PhD, Biology, 2015, University of Houston

URL: http://hdl.handle.net/10657/4876

► In this thesis, we investigated the mechanisms of two tumor-suppressive miRNAs in triple-negative breast cancer (TNBC). This undifferentiated subtype of breast cancer shows similarity of… (more)

▼ In this thesis, we investigated the mechanisms of two tumor-suppressive miRNAs in triple-negative breast cancer (TNBC). This undifferentiated subtype of breast cancer shows similarity of gene expression profiles as mammary epithelial progenitor cells HC11. Therefore, we first systematically explored the tumor suppressive miR-206 function in HC11 cell proliferation and differentiation. The levels of miR-206 are regulated during HC11 development. We demonstrated that miR-206 can block cell proliferation by inducing a G1-S cell cycle arrest. To elucidate how miR-206 modulates the HC11 development, we performed a microarray assay and found 106 genes affected by miR-206 could contribute to the cell cycle regulation. Furthermore, we found that miR-206 can also repress the epithelial-to-mesenchymal transition and promote the adipogenesis and cell differentiation through the Melk signaling pathways. The understanding of miR-206 function in mammary gland development leads us to study its tumor suppressive role in also undifferentiated TNBC. In TNBC, miR-206 is lost and one of its predicted target, Coronin actin-binding protein 1C (CORO1C) is up-regulated. CORO1C was found to be associated with TNBC patient survival and an anti-correlation between miR-206 and CORO1C was illustrated in both clinical samples and breast cancer cell lines. Furthermore, we shown the overexpression of miR-206 can suppress the level of CORO1C in TNBC cells and confirmed that the 3’UTR of CORO1C is directly targeted by miR-206. The miR-206-CORO1C pathway was then found to block cell proliferation, migration and also affect the actin filaments dynamics in TNBC cells. The dysregulation of actin cytoskeleton could result in the progression of tumor metastasis. Finally, we also demonstrate the anti-migratory effect of miR-200a in TNBC cells. miR-200a can directly silence the oncogene EPHA2 and thereby inhibiting the tumor metastatic potential. Our findings add important knowledge about miRNAs effect on mammary gland development and new approaches against TNBC. It also highlights the possibility to utilize tumor suppressive miRNA-206 and miRNA-200a as breast cancer biomarkers and miRNAs delivery therapy. Advisors/Committee Members: Williams, Cecilia M. (advisor), Frigo, Daniel E. (committee member), Gunaratne, Preethi H. (committee member), Landis, Melissa D. (committee member).

Subjects/Keywords: MicroRNAs (miRNA); Breast cancer

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APA (6^th Edition):

Wang, J. 1. (2015). The Mechanisms of Tumor-suppressive miRNAs in Mammary Stem Cell Development and Triple-negative Breast Cancer. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/4876

Chicago Manual of Style (16^th Edition):

Wang, Jun 1988-. “The Mechanisms of Tumor-suppressive miRNAs in Mammary Stem Cell Development and Triple-negative Breast Cancer.” 2015. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/4876.

MLA Handbook (7^th Edition):

Wang, Jun 1988-. “The Mechanisms of Tumor-suppressive miRNAs in Mammary Stem Cell Development and Triple-negative Breast Cancer.” 2015. Web. 16 Jan 2021.

Vancouver:

Wang J1. The Mechanisms of Tumor-suppressive miRNAs in Mammary Stem Cell Development and Triple-negative Breast Cancer. [Internet] [Doctoral dissertation]. University of Houston; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/4876.

Council of Science Editors:

Wang J1. The Mechanisms of Tumor-suppressive miRNAs in Mammary Stem Cell Development and Triple-negative Breast Cancer. [Doctoral Dissertation]. University of Houston; 2015. Available from: http://hdl.handle.net/10657/4876

University of Houston

3. Reins, Rose 1976-. Function of Vitamin D at the Ocular Surface and Its Role during Corneal Inflammation.

Degree: PhD, Biology and Biochemistry, 2015, University of Houston

URL: http://hdl.handle.net/10657/1981

► Although first recognized for its role in calcium regulation and bone health, there has been an explosion of research demonstrating that vitamin D is an… (more)

▼ Although first recognized for its role in calcium regulation and bone health, there has been an explosion of research demonstrating that vitamin D is an important modulator of the immune system. In the eye, studies have shown that deficiencies in vitamin D and genetic differences in vitamin D-related genes have a significant impact on the development of various ocular diseases. Vitamin D has been used effectively as a treatment for inflammatory conditions in many tissues, as well as in the eye, attenuating the progression of uveitis, for example. However, up until now, few studies have examined the role of vitamin D at the front part of the eye, the cornea. Maintenance of corneal transparency is essential for vision, and therefore, limiting inflammatory events is beneficial in this tissue. The work contained in this dissertation demonstrates that vitamin D is activated by corneal epithelial cells and is able to regulate gene expression in these cells, including enhancing antimicrobial peptide production. Vitamin D also modulates the inflammatory response to pattern recognition receptor stimulation, by increasing initial cytokine levels and then acting to dampen pro-inflammatory signals later in the response. In vivo, the use of topical vitamin D was explored both during experimental dry eye and in a mouse model of corneal wound healing. Although vitamin D increased tear production in normal mice, a protective effect on the ocular surface, wound healing was delayed and inflammatory signs augmented with vitamin D treatment after epithelial abrasion. These studies fill a gap in knowledge about vitamin D at the ocular surface and highlight the need for research into the immunomodulatory functions of the hormone in the ultimate goal of using vitamin D therapeutically for corneal inflammation. Advisors/Committee Members: McDermott, Alison M. (advisor), Burns, Alan R. (committee member), Frigo, Daniel E. (committee member), Gustafsson, Jan-Åke (committee member).

Subjects/Keywords: Vitamin D; Cornea; Ocular surface; Inflammation; Antimicrobial peptide; Wounding; Dry eye diseases; Immunomodulation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Reins, R. 1. (2015). Function of Vitamin D at the Ocular Surface and Its Role during Corneal Inflammation. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/1981

Chicago Manual of Style (16^th Edition):

Reins, Rose 1976-. “Function of Vitamin D at the Ocular Surface and Its Role during Corneal Inflammation.” 2015. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/1981.

MLA Handbook (7^th Edition):

Reins, Rose 1976-. “Function of Vitamin D at the Ocular Surface and Its Role during Corneal Inflammation.” 2015. Web. 16 Jan 2021.

Vancouver:

Reins R1. Function of Vitamin D at the Ocular Surface and Its Role during Corneal Inflammation. [Internet] [Doctoral dissertation]. University of Houston; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/1981.

Council of Science Editors:

Reins R1. Function of Vitamin D at the Ocular Surface and Its Role during Corneal Inflammation. [Doctoral Dissertation]. University of Houston; 2015. Available from: http://hdl.handle.net/10657/1981

University of Houston

4. -8379-9505. Modulation of Nuclear Receptor Functions in Breast and Pancreatic Cancers.

Degree: PhD, Cell and Molecular Biology, 2015, University of Houston

URL: http://hdl.handle.net/10657/5367

► Alcohol Regulates Genes that are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells. Pancreatic ductal adenocarcinoma (PDAC)… (more)

▼ Alcohol Regulates Genes that are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells. Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation. Intriguingly, LXR agonists exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC. The Antiproliferative Properties and Mechanisms of LXR Ligands on Pancreatic Ductal Adenocarcinoma Cells. Hereditary, hormonal, and behavioral factors contribute to the development of breast cancer. One modifiable behavioral factor, alcohol consumption, is linked to breast cancer risk. In this study we characterized molecular mechanisms of action of alcohol in estrogen receptor (ER)-positive breast cancer cells. Treatments with alcohol promoted cell proliferation, increased growth factor signaling, and up-regulated the transcription of the ER target gene GREB1. Microarray analysis following alcohol treatment identified a large number of alcohol-responsive genes, which were strongly associated with clinical outcomes in patients who received endocrine therapy. Correspondingly, alcohol treatment attenuated the anti-proliferative effects of the endocrine therapeutic drug tamoxifen in ER-positive breast cancer cells. To determine the contribution and functions of responsive genes, their differential expression in tumors were assessed between outcome groups. The proto-oncogene BRAF was identified as a novel alcohol- and estrogen-induced gene that showed higher expression in patients with poor outcomes. Knock-down of BRAF, moreover, prevented the proliferation of breast cancer cells. These findings not only highlight the mechanistic basis of the effects of alcohol on breast cancer cells and increased risks for disease incidents and recurrence, but may facilitate the discovery and characterization of novel oncogenic pathways and markers in breast cancer research and therapeutics. Advisors/Committee Members: Lin, Chin-Yo (advisor), Phillips, Kevin J. (committee member), Frigo, Daniel E. (committee member), Williams, Cecilia M. (committee member).

Subjects/Keywords: LXR; Pancreatic cancer; ER; Breast cancer; Alcohol

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APA (6^th Edition):

-8379-9505. (2015). Modulation of Nuclear Receptor Functions in Breast and Pancreatic Cancers. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/5367

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Chicago Manual of Style (16^th Edition):

-8379-9505. “Modulation of Nuclear Receptor Functions in Breast and Pancreatic Cancers.” 2015. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/5367.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

MLA Handbook (7^th Edition):

-8379-9505. “Modulation of Nuclear Receptor Functions in Breast and Pancreatic Cancers.” 2015. Web. 16 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Vancouver:

-8379-9505. Modulation of Nuclear Receptor Functions in Breast and Pancreatic Cancers. [Internet] [Doctoral dissertation]. University of Houston; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/5367.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Council of Science Editors:

-8379-9505. Modulation of Nuclear Receptor Functions in Breast and Pancreatic Cancers. [Doctoral Dissertation]. University of Houston; 2015. Available from: http://hdl.handle.net/10657/5367

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

University of Houston

5. Mehta, Fabiola Melissa 1985-. Suppression of Cervical Cancer by the Progesterone Receptor Signaling.

Degree: PhD, Biology, 2016, University of Houston

URL: http://hdl.handle.net/10657/3271

► Cervical cancer is the fourth-most common cancer in woman and fourth leading cause of cancer death worldwide. The majority of cervical cancer is associated with… (more)

▼ Cervical cancer is the fourth-most common cancer in woman and fourth leading cause of cancer death worldwide. The majority of cervical cancer is associated with high-risk human papillomaviruses (HPVs). Their tumorigenic potential stems mainly from viral oncoproteins E6 and E7, which are best known to inactivate p53 and pRb tumor suppressor, respectively. Epidemiological evidence suggests that, in addition to persistent HPV infections, other cofactors are required for cervical cancer. Multiple pregnancies and oral contraceptive use increases the risk for cervical cancer in HPV-infected women, implicating a role of estrogen and progesterone in cervical cancer. Prior studies utilizing an HPV transgenic mouse model expressing E6 and E7 (K14E6/K14E7) have demonstrated the requirement of estrogen receptor alpha (ERα) and estradiol (E2) for cervical carcinogenesis. Accumulating evidence suggests that ERα may be important for human cervical cancer. The role of progesterone and progesterone receptor (PR) in cervical cancer remains elusive. Our laboratory has demonstrated that PR agonist medroxyprogesterone acetate (MPA) promotes regression of cervical cancer and cervical intraepithelial neoplasia (CIN) in the K14E6/K14E7 mice. Goals of my dissertation project were to determine whether cervical cancer recurs after MPA therapy and whether epithelial PR is required for therapeutic effect of MPA. Using the K14E6/K14E7 mice, I found that cervical cancer recurred even if MPA treatment was continued, and recurring cervical cancer expressed PR but was refractory to MPA. In addition to PR, MPA interacts with other nuclear receptors including glucocorticoid receptor. Using the Cre/LoxP recombination system, I found that epithelial PR promoted apoptosis and inhibited proliferation in the cervical epithelium. I also determined that epithelial PR was required for MPA-mediated regression of cervical cancer, which was inhibited by E2. My results strongly support the hypothesis that epithelial PR is ligand-dependent tumor suppressor in cervical cancer. Approximately 33% of cervical cancer expresses PR. My results suggest that PR expression may not be sufficient to benefit from MPA therapy. My results also warrants further study to determine mechanism of recurrence and therapy resistance, which will facilitate the development of a better therapy for the disease. Advisors/Committee Members: Chung, Sang-Hyuk (advisor), Bawa-Khalfe, Tasneem (committee member), Frigo, Daniel E. (committee member), Weigel, Nancy L. (committee member).

Subjects/Keywords: Progesterone receptor; Cervical cancer; Female reproductive tract

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Mehta, F. M. 1. (2016). Suppression of Cervical Cancer by the Progesterone Receptor Signaling. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/3271

Chicago Manual of Style (16^th Edition):

Mehta, Fabiola Melissa 1985-. “Suppression of Cervical Cancer by the Progesterone Receptor Signaling.” 2016. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/3271.

MLA Handbook (7^th Edition):

Mehta, Fabiola Melissa 1985-. “Suppression of Cervical Cancer by the Progesterone Receptor Signaling.” 2016. Web. 16 Jan 2021.

Vancouver:

Mehta FM1. Suppression of Cervical Cancer by the Progesterone Receptor Signaling. [Internet] [Doctoral dissertation]. University of Houston; 2016. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/3271.

Council of Science Editors:

Mehta FM1. Suppression of Cervical Cancer by the Progesterone Receptor Signaling. [Doctoral Dissertation]. University of Houston; 2016. Available from: http://hdl.handle.net/10657/3271

University of Houston

6. Tennakoon, Jayantha 1969-. Impact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer.

Degree: PhD, Biology, 2013, University of Houston

URL: http://hdl.handle.net/10657/1027

► What mechanisms govern a cellular phenotype is a fascinating question for which answers are yet being sought. The work presented in this dissertation is an… (more)

▼ What mechanisms govern a cellular phenotype is a fascinating question for which answers are yet being sought. The work presented in this dissertation is an effort to address two fundamental questions, which relate to cellular transition of pluripotent stem cells to a differentiated state and the ability of prostate cancer to have increased proliferative potential. Dicer is an evolutionary conserved RNAse III type endoribonuclease enzyme, which plays a pivotal role in the biogenesis of microRNAs and silencing RNAs (siRNAs). Within the first chapter herein using in vitro cultures of embryonic stem cells, I show that loss of Dicer leads to changes in the ES cell epigenome resulting in a shift in transcriptionally favorable versus transcriptionally unfavorable histone modifications and thereby affect gene expression critical for precise cellular differentiation. In the second chapter, employing a combination of molecular biological and modern metabolomics approaches I show that androgen signaling deregulated in almost all forms of metastatic prostate cancers can lead to increased mitochondrial biogenesis and ATP production affording a distinct proliferative advantage. The underlying mechanism is linked to androgen mediated AMPK- PGC-1α signaling which results increased oxidative capacity in addition to elevated glycolytic capacity quite well established in numerous types of cancers. The pathway uncovered provides an interesting option for targeted therapeutics of prostatic cancers that are particularly resistant to androgen ablation therapies. Finally in the third chapter I show the significance of Dicer in maintaining expression levels of developmentally critical mammalian imprinted genes. The combined results of this thesis provide mechanistic insights into developmentally critical cellular pathways in embryonic stem cells and cancer having high potential to be manipulated in stem cell and molecular intervention based therapeutics. Advisors/Committee Members: Gunaratne, Preethi H. (advisor), Frigo, Daniel E. (advisor), Wells, Dan E. (committee member), Gao, Xiaolian (committee member), Zwaka, Thomas P. (committee member).

Subjects/Keywords: Dicer; Mouse embryonic stem cells; Epigenome; Androgen signaling; AMPK; PGC1a; Prostate cancer; Biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tennakoon, J. 1. (2013). Impact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/1027

Chicago Manual of Style (16^th Edition):

Tennakoon, Jayantha 1969-. “Impact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer.” 2013. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/1027.

MLA Handbook (7^th Edition):

Tennakoon, Jayantha 1969-. “Impact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer.” 2013. Web. 16 Jan 2021.

Vancouver:

Tennakoon J1. Impact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer. [Internet] [Doctoral dissertation]. University of Houston; 2013. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/1027.

Council of Science Editors:

Tennakoon J1. Impact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer. [Doctoral Dissertation]. University of Houston; 2013. Available from: http://hdl.handle.net/10657/1027

University of Houston

7. Cuko, Efrosini 1987-. Elucidating the Role of Glucose Metabolism in Prostate Cancer.

Degree: PhD, Cell and Molecular Biology, 2015, University of Houston

URL: http://hdl.handle.net/10657/5371

► Prostate cancer is a complex disease. Despite the progress in early detection and treatment, the progression to castration-resistant prostate cancer (CRPC) is inevitable for some… (more)

▼ Prostate cancer is a complex disease. Despite the progress in early detection and treatment, the progression to castration-resistant prostate cancer (CRPC) is inevitable for some patients and the survival window is only extended to approximately two-three years with current therapeutic options. Identifying new therapeutic targets for prostate cancer treatment is crucial. An important aspect of the tumor growth is metabolic rewiring. Androgens increase glucose uptake and subsequently glycolysis and PPP flux. I investigated how Androgen receptor (AR) signaling regulated the pentose phosphate pathway (PPP), a commonly overshadowed metabolic pathway. The activation of PPP happens in part via regulation of the rate-limiting enzyme of PPP, glucose-6-phosphate dehydrogenase (G6PD). G6PD was demonstrated to be regulated via an AR-mTOR signaling cascade and was important for proliferation, NADPH generation, ROS scavenging and ribose synthesis in prostate cancer cells. Further investigation led to the elucidation of the regulation of the committed step of glycolysis, phosphofructokinase-1 (PFK1). PFK1 is regulated allosterically via the metabolite fructose-2,6-bisphosphate. This metabolite is synthesized or degraded by the actions of phosphofructokinase fructose bisphosphate (PFKFB). Androgen receptor signaling, mTOR and AMPK regulate the transcription of PFKFB2 and PFKFB3. Additionally, the CAMKK2-AMPK signaling axis, which is regulated by AR, regulates the activity of PFKFB2 and PFKFB3 via phosphorylation. Pharmacological inhibition of PFKFB3 using PFK15 in CRPC AR+ and AR- prostate cancer cells demonstrated that PFK15 blocked glucose uptake, glycolysis and cell growth. These results highlight PFKFB2 and 3 potential as a therapeutic target in advanced prostate cancers. Finally, investigation of how AR signaling regulates glucose uptake to support an increase of the glycolytic and PPP flux has led to the identification of a new direct target of AR, SLC2A12 (GLUT12). GLUT12 is important for glucose uptake and subsequent cellular proliferation. Taken together, AR signaling cascades were demonstrated to work in concert with additional oncogenic pathways to augment multiple aspects of glucose metabolism for the purposes of supporting the energetic and biosynthetic needs of prostate cancer cells. As such, I propose targeting these newly identified metabolic pathways may offer a new therapeutic approach for the diagnosis and/or treatment of advanced prostate cancer. Advisors/Committee Members: Frigo, Daniel E. (advisor), Williams, Cecilia M. (committee member), Zhang, Xiaoliu Shaun (committee member), McGuire, Sean E. (committee member).

Subjects/Keywords: Prostate cancer; Pentose phosphate pathway; Glycolysis; Glucose transporters; AMPK; CaMKK2; PPP; G6PD; PFKFB2; PFKFB3; MTOR; GLUT12; TBC1D4

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cuko, E. 1. (2015). Elucidating the Role of Glucose Metabolism in Prostate Cancer. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/5371

Chicago Manual of Style (16^th Edition):

Cuko, Efrosini 1987-. “Elucidating the Role of Glucose Metabolism in Prostate Cancer.” 2015. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/5371.

MLA Handbook (7^th Edition):

Cuko, Efrosini 1987-. “Elucidating the Role of Glucose Metabolism in Prostate Cancer.” 2015. Web. 16 Jan 2021.

Vancouver:

Cuko E1. Elucidating the Role of Glucose Metabolism in Prostate Cancer. [Internet] [Doctoral dissertation]. University of Houston; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/5371.

Council of Science Editors:

Cuko E1. Elucidating the Role of Glucose Metabolism in Prostate Cancer. [Doctoral Dissertation]. University of Houston; 2015. Available from: http://hdl.handle.net/10657/5371

University of Houston

8. -9636-8146. Long Noncoding RNAs in Cardiac and Skeletal Muscle Differentiation during Mouse Embryogenesis.

Degree: PhD, Biology, 2017, University of Houston

URL: http://hdl.handle.net/10657/4789

► Development is a multistep process that involves a close co-ordination of gene regulatory networks. Lineage specification is a crucial step involved in embryogenesis and understanding… (more)

▼ Development is a multistep process that involves a close co-ordination of gene regulatory networks. Lineage specification is a crucial step involved in embryogenesis and understanding the significant steps involved in gene regulatory mechanisms is critical. Long non-coding RNAs, longer than 200 nucleotides have been identified as a new regulator of many molecular mechanisms involved in the development and pathological conditions. From the genome-wide transcriptome analysis of Mesp1-lineage reporter mouse ESC line (UH3), we identified mesoderm specific lncRNAs, from which we selected a subset of 12 lncRNAs for functional characterization. Of this, we identified lincRNA Platr14 to have a positive expression in vivo in cardiac plate and somites of E9.5 mouse embryos. Platr14 was seen enriched in vitro in the undifferentiated AB2.2 ES cell line, and the inhibition of Platr14 showed a decrease in the beating percentage of embryoid bodies which correlated with a deregulation of the mesoderm and cardiac-specific genes. Since Platr14 was enriched in the region of the myotome of E9.5 Embryos, we studied its role in myogenesis. Platr14 showed enrichment in skeletal muscle and the tongue in E15.5 embryonic mouse tissues. Knockdown of Platr14 in C2C12 mesenchymal cell line showed a deregulation of myogenic markers as well as a reduction in the fusion rate for the myotube formation. Though overexpression of Platr14 showed an up-regulation of the main myogenic markers, it did not show any significant change in the myotube formation rate. Strikingly, Platr14 overexpression in the terminal stages showed a repression in the expression of terminal myogenic markers. The whole transcriptome analysis by RNA-Sequencing of differentiating C2C12 myoblasts at day 2, showed a down-regulation of genes associated with the mesenchymal formation, somitogenesis, metabolism, cell migration, calcium transport and cell-cell signaling all related to developmental changes. In-silico analysis identified conservation of 3’ UTR of Platr14 across species as well as unique sites complementary to about 29 DNA binding sites of the mouse genome. Gene Ontology studies identified these DNA binding sites to have roles related to developmental processes. In this dissertation, we identified lincRNA Platr14, to have a novel role in mesoderm lineage driving the cardiac and skeletal myogenic differentiation. Advisors/Committee Members: Schwartz, Robert J. (advisor), Lin, Chin-Yo (committee member), Frigo, Daniel E. (committee member), Chen, Li (committee member), Cooney, Austin J. (committee member).

Subjects/Keywords: Long non coding RNA; RNA; Platr14; Cardiac; Skeletal myogenesis; Differentiation

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APA (6^th Edition):

-9636-8146. (2017). Long Noncoding RNAs in Cardiac and Skeletal Muscle Differentiation during Mouse Embryogenesis. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/4789

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Chicago Manual of Style (16^th Edition):

-9636-8146. “Long Noncoding RNAs in Cardiac and Skeletal Muscle Differentiation during Mouse Embryogenesis.” 2017. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/4789.

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Author name may be incomplete

MLA Handbook (7^th Edition):

-9636-8146. “Long Noncoding RNAs in Cardiac and Skeletal Muscle Differentiation during Mouse Embryogenesis.” 2017. Web. 16 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Vancouver:

-9636-8146. Long Noncoding RNAs in Cardiac and Skeletal Muscle Differentiation during Mouse Embryogenesis. [Internet] [Doctoral dissertation]. University of Houston; 2017. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/4789.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Council of Science Editors:

-9636-8146. Long Noncoding RNAs in Cardiac and Skeletal Muscle Differentiation during Mouse Embryogenesis. [Doctoral Dissertation]. University of Houston; 2017. Available from: http://hdl.handle.net/10657/4789

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

University of Houston

9. -3163-8114. Novel Mechanisms of Androgen Receptor Signaling in Prostate Cancer.

Degree: PhD, Biology, 2015, University of Houston

URL: http://hdl.handle.net/10657/4885

► Androgens regulate the physiological development of the prostate and the pathology of prostate cancer. Androgen-receptor (AR)-mediated transcriptional activity is a driver of prostate cancer (PCa)… (more)

▼ Androgens regulate the physiological development of the prostate and the pathology of prostate cancer. Androgen-receptor (AR)-mediated transcriptional activity is a driver of prostate cancer (PCa) progression. AR-induced transcriptional activity is a dynamic process that is regulated by the binding of ligands that induce distinct conformational changes in AR. These structural alterations lead to the differential recruitment of coregulators (coactivators or corepressors) that control the expression of specific subsets AR-regulated genes. Despite continual improvement in design and enhanced efficacy, PCa cells eventually become resistant to AR-antagonists and anti-androgen treatment. Therefore, in this dissertation, we have proposed and identified two novel mechanisms of harnessing AR-mediated gene transcription in PCa. First, we show that a stretch of proline residues located within the N-terminus of AR is a bona fide coregulator binding surface, the disruption of which reduces the androgen-dependent proliferation and migration of prostate cancer cells. Using T7 phage display, we identified a novel AR-interacting protein, SH3YL1, whose interaction with the receptor is dependent upon this polyproline domain. As with mutations within the AR polyproline domain, knockdown of SH3YL1 attenuated androgen-mediated cell growth and migration. RNA expression analysis revealed that SH3YL1 was required for the induction of a subset of AR-modulated genes. Notable was the observation that ubinuclein1 (UBN1), a key member of a histone H3.3 chaperone complex, was a transcriptional target of the AR/SH3YL1 complex, correlated with aggressive prostate cancer in patients, and was necessary for the maximal androgen-mediated proliferation and migration of prostate cancer cells. Collectively, these data highlight the importance of an amino-terminal activation domain, its associated coregulator, and downstream transcriptional targets in regulating cellular processes of pathological importance in prostate cancer. In the second approach of this dissertation, we studied the downstream AR targets that regulate autophagy. We have determined that 1) androgens regulate overall cell metabolism and cell growth, in part, by increasing autophagy in prostate cancer cells, 2) functional autophagy was clinically detected in metastatic, castration-resistant cancers but not treatment-naïve, localized tumors and 3) autophagy is required for prostate cancer progression in preclinical animal models. Inhibition of autophagy using molecular inhibitors significantly abrogated androgen-induced prostate cancer cell/tumor growth. Autophagy and subsequent cell growth is potentiated by androgen-mediated increases in the expression and activity of several core autophagy genes, including ULK1, ULK2, AT4B, ATG4D, and TFEB. We identify these five genes as direct targets of the androgen receptor (AR) in prostate cancer. Moreover, expression of these five genes is essential for maximal androgen-mediated autophagy and cell proliferation. These findings demonstrate a role… Advisors/Committee Members: Frigo, Daniel E. (advisor), Sater, Amy K. (committee member), Warner, Margaret (committee member), Merchant, Fatima Aziz (committee member).

Subjects/Keywords: Androgen receptor; Prostate cancer; SH3YL1; Ubinuclein1 (UBN1); Autophagy; Polyproline

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APA (6^th Edition):

-3163-8114. (2015). Novel Mechanisms of Androgen Receptor Signaling in Prostate Cancer. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/4885

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Chicago Manual of Style (16^th Edition):

-3163-8114. “Novel Mechanisms of Androgen Receptor Signaling in Prostate Cancer.” 2015. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/4885.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

MLA Handbook (7^th Edition):

-3163-8114. “Novel Mechanisms of Androgen Receptor Signaling in Prostate Cancer.” 2015. Web. 16 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Vancouver:

-3163-8114. Novel Mechanisms of Androgen Receptor Signaling in Prostate Cancer. [Internet] [Doctoral dissertation]. University of Houston; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/4885.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

Council of Science Editors:

-3163-8114. Novel Mechanisms of Androgen Receptor Signaling in Prostate Cancer. [Doctoral Dissertation]. University of Houston; 2015. Available from: http://hdl.handle.net/10657/4885

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete

University of Houston

10. Son, Jieun 1985-. Mechanism of Estrogen Receptor Alpha in Cervical Carcinogenesis.

Degree: PhD, Cell and Molecular Biology, 2017, University of Houston

URL: http://hdl.handle.net/10657/4602

► Most cervical cancers are associated with high-risk human papillomaviruses (HPVs). HPVs display tumorigenic functions in host cells mainly through viral oncogenes E6 and E7 that… (more)

▼ Most cervical cancers are associated with high-risk human papillomaviruses (HPVs). HPVs display tumorigenic functions in host cells mainly through viral oncogenes E6 and E7 that are best known to inhibit p53 and pRb tumor suppressor, respectively. However, HPV infection alone is not sufficient to induce cervical cancer. Other cofactors have been identified. Long-term use of oral contraceptives and multiple full-term pregnancies increase the risk of cervical cancer in women with HPV infection. Prolonged treatment of estrogen is required for initiation and maintenance of cervical cancer in HPV transgenic mice expressing E6 and E7. Genetic deletion of estrogen receptor alpha (ERα) inhibits the development of cervical cancer in the same mouse models. While these findings highlight the importance of estrogen and ERα in cervical carcinogenesis, there is little understanding of their mechanism of action. My dissertation seeks to explain how ERα contributes to cervical carcinogenesis. The main questions addressed in this dissertation are: (1) Is the DNA- binding domain (DBD) of ERα required for cervical carcinogenesis? (2) Is epithelial ERα required for cervical carcinogenesis? Genetically engineered mouse models expressing a DBD mutant or allowing a conditional deletion of ERα were used to answer these questions. The data in Chapter 1 demonstrate that point mutations within ERα DBD reduce estrogen-induced cell proliferation in the cervical epithelium. In HPV transgenic mice, ERα DBD is necessary for initiation of cervical cancer. In Chapter 2, I address the effect of specific deletion of ERα in the epithelial compartment on cervical carcinogenesis. Using epithelium-specific knockout mice, I conclude that epithelial ERα is not absolutely required for estrogen-induced cervical cancer in HPV transgenic mice. I should also note that, although almost all epithelial ERα-deficient HPV transgenic mice developed cervical neoplastic diseases, a smaller fraction of mice developed cervical cancer compared to epithelial ERα-sufficient control mice. These results are in accord with previous observations that stromal ERα signaling is required for progression of cervical neoplasia to cancer in the same mouse model. Lastly my dissertation gives a description on the establishment of a new orthotopic mouse model for human cervical cancer (Chapter 3). This novel preclinical model will be valuable in further studies to determine efficiency of drug candidates such as anti-estrogenic reagents in treating human cervical cancer. Advisors/Committee Members: Chung, Sang-Hyuk (advisor), Frigo, Daniel E. (committee member), Fuqua, Suzanne, A. W. (committee member), Lin, Chin-Yo (committee member).

Subjects/Keywords: Estrogen receptor alpha; Cervical cancer

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APA (6^th Edition):

Son, J. 1. (2017). Mechanism of Estrogen Receptor Alpha in Cervical Carcinogenesis. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/4602

Chicago Manual of Style (16^th Edition):

Son, Jieun 1985-. “Mechanism of Estrogen Receptor Alpha in Cervical Carcinogenesis.” 2017. Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/4602.

MLA Handbook (7^th Edition):

Son, Jieun 1985-. “Mechanism of Estrogen Receptor Alpha in Cervical Carcinogenesis.” 2017. Web. 16 Jan 2021.

Vancouver:

Son J1. Mechanism of Estrogen Receptor Alpha in Cervical Carcinogenesis. [Internet] [Doctoral dissertation]. University of Houston; 2017. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/4602.

Council of Science Editors:

Son J1. Mechanism of Estrogen Receptor Alpha in Cervical Carcinogenesis. [Doctoral Dissertation]. University of Houston; 2017. Available from: http://hdl.handle.net/10657/4602

11. Swaby, Tyrek Nesta 1982-. Design and Synthesis of 4-Hydroxy Proline Based Library for Pharmaceutical Uses.

Degree: MS, Chemistry, 2013, University of Houston

URL: http://hdl.handle.net/10657/838

► Trans-4-hydroxy proline is readily accessible, stereochemically rich molecule that offers multiple sites for functionality. This functionality can be used to attach different pharmacophores in an… (more)

Subjects/Keywords: Proline; Small Molecule Library; Drug design; Scaffold Modification; Chemistry

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APA (6^th Edition):

Swaby, T. N. 1. (2013). Design and Synthesis of 4-Hydroxy Proline Based Library for Pharmaceutical Uses. (Masters Thesis). University of Houston. Retrieved from http://hdl.handle.net/10657/838

Chicago Manual of Style (16^th Edition):

Swaby, Tyrek Nesta 1982-. “Design and Synthesis of 4-Hydroxy Proline Based Library for Pharmaceutical Uses.” 2013. Masters Thesis, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/838.

MLA Handbook (7^th Edition):

Swaby, Tyrek Nesta 1982-. “Design and Synthesis of 4-Hydroxy Proline Based Library for Pharmaceutical Uses.” 2013. Web. 16 Jan 2021.

Vancouver:

Swaby TN1. Design and Synthesis of 4-Hydroxy Proline Based Library for Pharmaceutical Uses. [Internet] [Masters thesis]. University of Houston; 2013. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/838.

Council of Science Editors:

Swaby TN1. Design and Synthesis of 4-Hydroxy Proline Based Library for Pharmaceutical Uses. [Masters Thesis]. University of Houston; 2013. Available from: http://hdl.handle.net/10657/838

University of Houston

12. -5121-5234. Inhibition of Fatty Acid Amide Hydrolase Increases Rates of Apoptosis in Cell Line Models of DLBCL and Breast Cancer.

Degree: MS, Biomedical Engineering, University of Houston

URL: http://hdl.handle.net/10657/3576

► Despite recent advances in cancer treatment, cancers with high heterogeneity such as DLBCL and breast cancer remain difficult to treat, with many patients having few… (more)

Subjects/Keywords: FAAH; Fatty Acid Amide Hydrolase; DLBCL; Breast cancer; CB1; CB2; Endocannabinoids; Apoptosis; URB 597

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APA (6^th Edition):

-5121-5234. (n.d.). Inhibition of Fatty Acid Amide Hydrolase Increases Rates of Apoptosis in Cell Line Models of DLBCL and Breast Cancer. (Masters Thesis). University of Houston. Retrieved from http://hdl.handle.net/10657/3576

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
No year of publication.

Chicago Manual of Style (16^th Edition):

-5121-5234. “Inhibition of Fatty Acid Amide Hydrolase Increases Rates of Apoptosis in Cell Line Models of DLBCL and Breast Cancer.” Masters Thesis, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/3576.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
No year of publication.

MLA Handbook (7^th Edition):

-5121-5234. “Inhibition of Fatty Acid Amide Hydrolase Increases Rates of Apoptosis in Cell Line Models of DLBCL and Breast Cancer.” Web. 16 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
No year of publication.

Vancouver:

-5121-5234. Inhibition of Fatty Acid Amide Hydrolase Increases Rates of Apoptosis in Cell Line Models of DLBCL and Breast Cancer. [Internet] [Masters thesis]. University of Houston; [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/3576.

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
No year of publication.

Council of Science Editors:

-5121-5234. Inhibition of Fatty Acid Amide Hydrolase Increases Rates of Apoptosis in Cell Line Models of DLBCL and Breast Cancer. [Masters Thesis]. University of Houston; Available from: http://hdl.handle.net/10657/3576

Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
No year of publication.

University of Houston

13. Khan, Ayesha 1985-. mTOR-Mediated Regulation of Metabolic Pathways in Prostate Cancer.

Degree: MS, Biology, University of Houston

URL: http://hdl.handle.net/10657/3567

► Metabolic reprogramming is one of the key features of many cancers including prostate cancer. Interestingly, most prostate cancers demonstrate a marked shift towards increased mitochondrial… (more)

▼ Metabolic reprogramming is one of the key features of many cancers including prostate cancer. Interestingly, most prostate cancers demonstrate a marked shift towards increased mitochondrial metabolism following tumorigenesis. To that end, metabolic signatures of the tricarboxylic acid cycle (TCA) cycle, oxidative phosphorylation (OXPHOS) and the hexosamine biosynthetic pathway (HBP) correlate with cancer progression. Recent studies indicate that pharmacological inhibition of key steps in these metabolic pathways block cancer cell growth in vitro and disease progression in vivo. Therefore, understanding the mechanisms that lead to these metabolic alterations could yield new therapeutic targets. Here, we hypothesized that the mTOR-signaling pathway, a master regulator of metabolism and known oncogenic signal in prostate cancer, promoted prostate-cancer growth and progression by regulating pyruvate dehydrogenase, a key enzyme that links glycolysis to the TCA cycle and by inhibiting HBP. We used mass spectrometry-based approaches to quantify the levels of glycolytic, TCA cycle and HBP intermediates upon pharmacological inhibition of mTORC1. We also studied the effects on prostate- cancer cell growth following inhibition of pyruvate dehydrogenase and glutamine-fructose-6-phosphate transaminase 1, which is the rate-limiting enzyme of HBP. We show that upon pharmacological inhibition of mTORC1 the levels of pyruvate are increased in a castration-resistant cell model of prostate cancer (CRPC) while the levels of downstream intermediates of TCA cycle are decreased. On the other hand, the levels of downstream HBP metabolites are increased. This suggests that mTORC1 regulates flux through these metabolic pathways. Additionally, we demonstrate that siRNA-mediated silencing of pyruvate dehydrogenase decreased prostate cancer cell proliferation and survival whereas siRNA-mediated silencing of glutamine-fructose-6-phosphate trans-aminase 1 (GFPT1, increased prostate cancer cell growth. Collectively, our data indicate that mTORC1 increases flux into the TCA cycle via PDH and promotes prostate cancer cell growth and survival. mTORC1 also inhibits the HBP, leading to an oncogenic shift that reroutes glucose potentially toward glycolysis and the pentose phosphate pathway. Advisors/Committee Members: Frigo, Daniel E. (advisor), Chung, Sang-Hyuk (committee member), Chang, Jeffrey T. (committee member), Sater, Amy K. (committee member).

Subjects/Keywords: Prostate; Pathways

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APA (6^th Edition):

Khan, A. 1. (n.d.). mTOR-Mediated Regulation of Metabolic Pathways in Prostate Cancer. (Masters Thesis). University of Houston. Retrieved from http://hdl.handle.net/10657/3567

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Chicago Manual of Style (16^th Edition):

Khan, Ayesha 1985-. “mTOR-Mediated Regulation of Metabolic Pathways in Prostate Cancer.” Masters Thesis, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/3567.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

MLA Handbook (7^th Edition):

Khan, Ayesha 1985-. “mTOR-Mediated Regulation of Metabolic Pathways in Prostate Cancer.” Web. 16 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Khan A1. mTOR-Mediated Regulation of Metabolic Pathways in Prostate Cancer. [Internet] [Masters thesis]. University of Houston; [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/3567.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Council of Science Editors:

Khan A1. mTOR-Mediated Regulation of Metabolic Pathways in Prostate Cancer. [Masters Thesis]. University of Houston; Available from: http://hdl.handle.net/10657/3567

Note: this citation may be lacking information needed for this citation format:
No year of publication.

University of Houston

14. Nikollo, Foti 1986-. Exploring the Tumor Suppressive Roles of Estrogen Receptor β in Lung and Breast Cancer.

Degree: PhD, Biochemistry, University of Houston

URL: http://hdl.handle.net/10657/2043

► Estrogens represent a subclass of steroid hormones that by regulating cell growth and differentiation, influence normal physiology as well as pathology. The effects of estrogen… (more)

▼ Estrogens represent a subclass of steroid hormones that by regulating cell growth and differentiation, influence normal physiology as well as pathology. The effects of estrogen are mediated by two members of the nuclear receptor superfamily, Estrogen Receptor α (ERα) and ERβ. A plethora of studies have shown that ERα and ERβ exert opposite effects on cancer development and progression by eliciting distinct transcriptional responses and differentially influencing cellular processes such as cell proliferation, apoptosis, and migration. The present study focused on the potential role of ERβ in affecting development and progression of the two most commonly diagnosed cancers in men and women, lung and breast cancer, respectively. Our studies revealed that upregulation of wild-type ERβ (ERβ1), but not the splice variant ERβ2, reduces proliferation and enhances apoptosis in non-small cell lung cancer (NSCLC) cells. ERβ1 was found to induce apoptosis by stimulating the intrinsic apoptotic pathway that involved upregulation of the pro-apoptotic factor BIM and downregulation of components of the growth factor signaling pathway. Manipulation of EGFR and RAS expression and activity in ERβ1-expressing cells revealed the central role of oncogenic RAS signaling in ERβ1-mediated pro-apoptotic phenotype and EGFR regulation. In addition, our studies demonstrated that ERβ1 sensitizes NSCLC cells to chemotherapeutic agents. Upregulation of ERβ1 decreased the viability of doxorubicin- and etoposide-treated NSCLC cells by inducing G2/M phase cell cycle arrest. In response to treatment, ERβ1-expressing cells had increased p-Chk1 levels, an indicator of activated DNA damage response, compared with the control cells. Finally, we showed that ERβ1 represses epithelial to mesenchymal transition (EMT) and invasion of basal-like breast cancer cells both in vitro and in vivo. ERβ1 impeded EMT by downregulating EGFR. EGFR downregulation in ERβ1-expressing cells was associated with the stabilization of the ubiquitin ligase c-Cbl-EGFR complexes that led to increased ubiquitylation and degradation of the activated receptor. In conclusion, our studies have unveiled the important role of ERβ in regulating crucial processes of lung and breast cancer development and progression and propose ERβ as a potential biomarker for predicting metastasis in breast cancer and response to treatment in NSCLC. Advisors/Committee Members: Gustafsson, Jan-Åke (advisor), Thomas, Christoforos (committee member), Schwartz, Robert J. (committee member), Frigo, Daniel E. (committee member), Webb, Paul (committee member).

Subjects/Keywords: Estrogen receptor beta; EGFR; NSCLC; RAS; DNA damage response; P53; EMT; Basal-like; E-cadherin

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APA (6^th Edition):

Nikollo, F. 1. (n.d.). Exploring the Tumor Suppressive Roles of Estrogen Receptor β in Lung and Breast Cancer. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/2043

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Chicago Manual of Style (16^th Edition):

Nikollo, Foti 1986-. “Exploring the Tumor Suppressive Roles of Estrogen Receptor β in Lung and Breast Cancer.” Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/2043.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

MLA Handbook (7^th Edition):

Nikollo, Foti 1986-. “Exploring the Tumor Suppressive Roles of Estrogen Receptor β in Lung and Breast Cancer.” Web. 16 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Nikollo F1. Exploring the Tumor Suppressive Roles of Estrogen Receptor β in Lung and Breast Cancer. [Internet] [Doctoral dissertation]. University of Houston; [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/2043.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Council of Science Editors:

Nikollo F1. Exploring the Tumor Suppressive Roles of Estrogen Receptor β in Lung and Breast Cancer. [Doctoral Dissertation]. University of Houston; Available from: http://hdl.handle.net/10657/2043

Note: this citation may be lacking information needed for this citation format:
No year of publication.

University of Houston

15. Bado, Igor Landry 1986-. Understanding the Tumor Suppressive Functions of Estrogen Receptor β in Breast Cancer.

Degree: PhD, Biology, University of Houston

URL: http://hdl.handle.net/10657/3620

► Breast cancer is a heterogeneous disease with regard to clinical outcome and molecular characteristics. Some breast cancers are more aggressive because they express mutant proteins… (more)

▼ Breast cancer is a heterogeneous disease with regard to clinical outcome and molecular characteristics. Some breast cancers are more aggressive because they express mutant proteins with potent oncogenic functions including mutant p53 proteins with gain of functions. Such tumors are often resistant to therapies. Accumulating data show positive correlations between ERβ1 and better survival, indicating more important roles of the receptor in breast cancer. First, we investigated the role of ERβ in triple negative breast cancer cells (TNBCs) that are mutant for p53. These cells are derived from very aggressive cancers with highly metastatic and chemoresistant properties. TNBC are negative for ERα, PR, and Her2, and there is no effective targeted therapy. Despite the lack of ERα, a significant number of TNBCs express ERβ. ERβ1 displays anti-migratory, anti-invasive, and anti-metastatic properties. However, the mechanism underlying its function is not well understood. Using molecular technics, we found that ERβ1 opposes mutant p53 gain-of-function through direct interaction. Most importantly, we found that ERβ1 can use mutant p53 as a co-factor to alter gene transcription. Further, the ERβ1-induced epithelial transformation was p63-dependent, suggesting an association between ERβ1, mutant p53 and p63. Second, we investigated the role of ERβ in ERα-positive breast cancer cells. These cells are derived from less aggressive tumors that respond better to hormonal therapy. ERα-positive breast cancers often express wild-type p53, yet p53 tumor suppressive function is inactivated. Several factors including ERα have been found to inhibit wild-type p53 activity. Previous studies have shown anti-proliferative responses following upregulation of ERβ1 in ERα-positive breast cancer cells. ERβ1 was also shown to correlate with better overall and disease-free survival in patients with ERα-positive breast cancer especially after hormonal therapy. Still, the mechanism through which ERβ1 associates with improved prognosis had yet to be investigated. We show that ERβ1 enhances wild-type p53 activity in ERα-positive cells. Further, we found that ERβ1-specific ligands can affect p53 transcriptional activity. Overall, we were able to suggest some novel mechanisms through which ERβ1 elicits its tumor suppressive function and propose ERβ1 as a potential good marker and target for breast cancer treatment. Advisors/Committee Members: Gustafsson, Jan-Åke (advisor), Thomas, Christoforos (committee member), Webb, Paul (committee member), Lin, Chin-Yo (committee member), Frigo, Daniel E. (committee member).

Subjects/Keywords: Breast cancer; Cancer; Triple negative breast cancer cells (TNBC); ERβ1; P53; P63; EMT; Invasion; Metastasis; Luminal breast cancer; ERα

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APA (6^th Edition):

Bado, I. L. 1. (n.d.). Understanding the Tumor Suppressive Functions of Estrogen Receptor β in Breast Cancer. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/3620

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Chicago Manual of Style (16^th Edition):

Bado, Igor Landry 1986-. “Understanding the Tumor Suppressive Functions of Estrogen Receptor β in Breast Cancer.” Doctoral Dissertation, University of Houston. Accessed January 16, 2021. http://hdl.handle.net/10657/3620.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

MLA Handbook (7^th Edition):

Bado, Igor Landry 1986-. “Understanding the Tumor Suppressive Functions of Estrogen Receptor β in Breast Cancer.” Web. 16 Jan 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Bado IL1. Understanding the Tumor Suppressive Functions of Estrogen Receptor β in Breast Cancer. [Internet] [Doctoral dissertation]. University of Houston; [cited 2021 Jan 16]. Available from: http://hdl.handle.net/10657/3620.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Council of Science Editors:

Bado IL1. Understanding the Tumor Suppressive Functions of Estrogen Receptor β in Breast Cancer. [Doctoral Dissertation]. University of Houston; Available from: http://hdl.handle.net/10657/3620

Note: this citation may be lacking information needed for this citation format:
No year of publication.

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