Role of BNIP3 in proliferation and hypoxia-induced autophagy: implications for personalized cancer therapies.
Autophagy is a regulated degradation pathway functioning in both cell survival and cell death. Its role in cancer is controversial because autophagy can be either protective or destructive to tumor cells, depending on individual genetic signatures and treatment conditions. Hypoxia is common in solid tumors, correlating with chemoresistance and poor prognosis. We have detected autophagic cell death in hypoxic cancer cells occurring independently of apoptosis through a mechanism involving the hypoxia-inducible protein, Bcl-2/E1B-nineteen kilodalton interacting protein (BNIP3). Loss of BNIP3 was protective against hypoxia-induced autophagy and cell death. Unexpectedly, BNIP3 ablation also caused differential cell cycle progression in vitro and increased cellularity in vivo. Collectively, these results support the emerging theory that autophagy could be effectively targeted as an alternative cell death pathway in hypoxic and/or apoptosis-resistant tumors. Furthermore, our data suggest that BNIP3 may be a potential target molecule in this pathway.
Azad
Meghan B
MB
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada. meghan.azad@hotmail.com
Gibson
Spencer B
SB
D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*
C090121:BNIP3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins