Role of Autophagy in Cancer

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DESCRIPTION (provided by applicant): Autophagy is a catabolic process whereby cellular organelles and bulk cytoplasm are targeted for degradation in lysosomes. Recent evidence suggests that autophagy is a survival pathway necessary to sustain mammalian viability during periods of starvation, yet other evidence suggests that progressive autophagy can be a means to cell death if carried out to completion. Furthermore, constitutive autophagy is required to limit the accumulation of polyubiquitinated proteins in neuronal cells to prevent cellular degeneration. Thus autophagy is a homeostatic mechanism regulating the turnover of long-lived or damaged proteins and organelles that additionally functions to buffer metabolic stress during periods of nutrient limitation. Autophagy also plays a role in oncogenesis, although the mechanism is unknown. Allelic loss of the essential autophagy gene beclin1 is found with high frequency in human breast, ovarian and prostate cancers, and beclin1 mice are tumor prone, suggesting that autophagy is a tumor suppression mechanism. We have found that defects in apoptosis allow long-term cellular survival of immortal baby mouse kidney epithelial (iBMK) cells or mouse mammary epithelial cells (iMMECs) through autophagy. Moreover, autophagy localizes in tumors to regions of metabolic stress, and deficient autophagy compromises the survival to metabolic stress while promoting necrotic cell death, inflammation and tumor progression. These findings indicate, paradoxically, that loss of a survival pathway is oncogenic. While deficient autophagy reduces survival to starvation, this impaired cellular fitness is also associated with elevated DNA damage, gene amplification, chromosome gains and losses, and aneuploidy, suggesting that failure to maintain metabolism promotes genome instability. We thereby propose that autophagy functions to protect the genome, explaining the paradox: reduced cellular survival in autophagy defective cells is overcome by an increased mutation rate that drives tumor progression. We propose to determine how autophagy occurs, identify the mechanism of genome damage, and establish the role of chromosome instability caused by deficient autophagy in tumor progression. We specifically propose that autophagy is required to eliminate damaged proteins and organelles during metabolic stress, and failure to do so results in oxidative damage, mutations and tumor progression. PUBLIC HEALTH RELEVANCE: Determining how cancer cells defeat intrinsic suicide pathways and survive long periods of starvation only to resume growth and to progress to aggressive, treatment refractory disease is poorly understood. We have identified the catabolic, cellular "self eating" cannibalistic process of autophagy as a survival pathway utilized by solid tumor cells to survive starvation and protect their genome from mutations. We propose to establish the mechanism of autophagy and its consequence to cancer progression and therapeutic response.