Role of autophagy in cancer: management of metabolic stress.
Human breast, ovarian, and prostate tumors display allelic loss of the essential autophagy gene beclin1 with high frequency, and an increase in the incidence of tumor formation is observed in beclin1(+/-) mutant mice. These findings suggest a role for beclin1 and autophagy in tumor suppression; however, the mechanism by which this occurs has been unclear. Autophagy is a bulk degradation process whereby organelles and cytoplasm are engulfed and targeted to lysosomes for proteolysis,(1,2) There is evidence that autophagy sustains cell survival during nutrient deprivation through catabolism, but also that autophagy is a means of achieving cell death when executed to completion. If or how either of these diametrically opposing functions proposed for autophagy may be related to tumor suppression is unknown. We found that metabolic stress is a potent trigger of apoptotic cell death, defects in which enable long-term survival that is dependent on autophagy both in vitro and in tumors in vivo.(3) These findings raise the conundrum whereby inactivation of a survival pathway (autophagy) promotes tumorigenesis. Interestingly, when cells with defects in apoptosis are denied autophagy, this creates the inability to tolerate metabolic stress, reduces cellular fitness, and activates a necrotic pathway to cell death. This necrosis in tumors is associated with inflammation and enhancement of tumor growth, due to the survival of a small population of surviving, but injured, cells in a microenvironment that favors oncogenesis. Thus, by sustaining metabolism through autophagy during periods of metabolic stress, cells can limit energy depletion, cellular damage, and cell death by necrosis, which may explain how autophagy can prevent cancer, and how loss of a survival function can be tumorigenic.
Jin
Shengkan
S
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Newark, NJ 08854, USA. jinsh@umdnj.edu
White
Eileen
E
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction