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Author
Title Role of autophagy in cancer
URL
Publication Date
Degree PhD
Discipline/Department Biochemistry
Degree Level doctoral
University/Publisher Rutgers University
Abstract

(Macro)autophagy is a catabolic process whereby intracellular components are enclosed into autophagosomes and delivered to lysosomes for degradation. Constitutive activity of autophagy contributes to turnover of proteins and organelles, ensuring the quality control of cellular components. Autophagy also can be induced by starvation or other stresses. This activity serves to provide internal resources to sustain metabolism and to prevent accumulation of detrimental substances. Therefore, autophagy is critical for cells to maintain homeostasis and to survive stress. Tumors are often subjected to metabolic stress due to insufficient vascularization. Autophagy is induced and localizes to these hypoxic regions where it supports survival. In aggressive tumors, the increased metabolic demand of rapid proliferation and growth may augment the dependency of cells on autophagy. In addition, autophagy that is induced by cancer therapy may be utilized by tumor cells for survival and be counterproductive to therapeutic efficacy. In this work, we tested the hypothesis that autophagy enables tumor cell survival and tumorigenesis in two different settings and addressed the underlying mechanism by which this occurs. First, we demonstrated that autophagy is required for viability in starvation and tumorigenicity of cells with oncogenic Ras activation. In these cells, defective autophagy caused abnormal mitochondria accumulation and reduced mitochondrial functionality in starvation associated with reduced energy charge. Since mitochondrial function is required for survival during starvation, we reasoned that autophagy supports survival and tumorigenicity of Ras-expressing cells by maintaining mitochondrial functionality. We also demonstrated that autophagy maintained mitochondrial function by preserving functional mitochondrial pools through mitophagy as well as by providing substrates for mitochondrial bioenergetic production under stress, thereby identifying autophagy and mitophagy as potential targets for treatment of cancers with oncogenic Ras activation. Second, we examined the significance of the mTOR inhibition-induced autophagy in counteracting the efficacy of the mTOR inhibitor CCI-779, which has shown temporary effectiveness in clinical treatment of human renal cell carcinoma. We demonstrated that mTOR inhibition promoted autophagy-mediated stress tolerance. Inhibition of autophagy with chloroquine enhanced the cytotoxicity of CCI-779 in vitro and in allograft tumors in mice. We further demonstrated that autophagy promoted cell survival in CCI-779-treated cells by providing alternative substrates for mitochondrial metabolism and suppressing reactive oxygen species production. This result justified a combination of autophagy inhibition with mTOR inhibitors in cancer therapy.

Subjects/Keywords Cancer cells – Growth – Regulation; Cancer – Treatment
Contributors Chen, Hsin-Yi, 1977- (author); White, Eileen (chair); Jin, Shengkan (internal member); Karantza, Vassiliki (internal member); Gélinas, Céline (outside member)
Language en
Country of Publication us
Format xi, 128 p. : ill.
Record ID oai:example.org:rutgers-lib:31021
Other Identifiers rutgers-lib:31021; ETD_3095; doi:10.7282/T3SJ1K79
Repository rutgers
Date Indexed 2021-02-13

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