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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Salnikow, Konstantin
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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Strohecker, Anne M; White, Eileen (2014) Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism. Autophagy 10:384-5
Karsli-Uzunbas, Gizem; Guo, Jessie Yanxiang; Price, Sandy et al. (2014) Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov 4:914-27
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Andrianasolo, Eric H; Haramaty, Liti; White, Eileen et al. (2014) Mode of action of diterpene and characterization of related metabolites from the soft coral, Xenia elongata. Mar Drugs 12:1102-15
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Strohecker, Anne M; White, Eileen (2014) Targeting mitochondrial metabolism by inhibiting autophagy in BRAF-driven cancers. Cancer Discov 4:766-72
Guo, Jessie Yanxiang; Karsli-Uzunbas, Gizem; Mathew, Robin et al. (2013) Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev 27:1447-61
White, Eileen (2013) Exploiting the bad eating habits of Ras-driven cancers. Genes Dev 27:2065-71
Strohecker, Anne M; Guo, Jessie Yanxiang; Karsli-Uzunbas, Gizem et al. (2013) Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov 3:1272-85
White, Eileen (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12:401-10

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