Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis.
Defective apoptosis renders immortalized epithelial cells highly tumorigenic, but how this is impacted by other common tumor mutations is not known. In apoptosis-defective cells, inhibition of autophagy by AKT activation or by allelic disruption of beclin1 confers sensitivity to metabolic stress by inhibiting an autophagy-dependent survival pathway. While autophagy acts to buffer metabolic stress, the combined impairment of apoptosis and autophagy promotes necrotic cell death in vitro and in vivo. Thus, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors, but this necrosis is associated with inflammation and accelerated tumor growth. Thus, autophagy may function in tumor suppression by mitigating metabolic stress and, in concert with apoptosis, by preventing death by necrosis.
Degenhardt
Kurt
K
Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, New Jersey 08854, USA.
Mathew
Robin
R
Beaudoin
Brian
B
Bray
Kevin
K
Anderson
Diana
D
Chen
Guanghua
G
Mukherjee
Chandreyee
C
Shi
Yufang
Y
Gélinas
Céline
C
Fan
Yongjun
Y
Nelson
Deirdre A
DA
Jin
Shengkan
S
White
Eileen
E
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009336:Necrosis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D052002:NF-kappa B p50 Subunit; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt