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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA130893-03
Application #
7808060
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
2008-07-01
Project End
2013-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$317,491
Indirect Cost
Name
Rutgers University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
(2016) Women in Metabolism: Part IV. Cell Metab 24:767-770
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Santanam, Urmila; Banach-Petrosky, Whitney; Abate-Shen, Cory et al. (2016) Atg7 cooperates with Pten loss to drive prostate cancer tumor growth. Genes Dev 30:399-407
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Guo, Jessie Yanxiang; White, Eileen (2016) Autophagy, Metabolism, and Cancer. Cold Spring Harb Symp Quant Biol 81:73-78

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