AMP kinase signaling determines whether c-Jun N-terminal kinase promotes survival or apoptosis during glucose deprivation.
As solid tumors outgrow the surrounding vasculature, they encounter microenvironments with a limited supply of nutrients. Therefore, in order to survive, tumor cells need to adapt to glucose-deprived environments. In the present study, we examined the signaling pathways that lead to cancer cell survival in response to glucose deprivation. We primarily focused on the roles of adenosine monophosphate-activated protein kinase (AMPK), its upstream kinase LKB1 and c-Jun N-terminal kinase (JNK). Herein, we showed that in DU145 human prostate carcinomas, glucose deprivation activated JNK with biphasic kinetics. We demonstrated that the early phase of JNK activation promoted cell survival, whereas the late phase of JNK activation induced apoptosis. Our data further showed that AMPK relayed a survival signal transmitted by early activation of JNK and that the sustained AMPK signal in turn inhibited the proapoptotic property of JNK via a negative feedback mechanism involving reactive oxygen species. We induced this negative feedback inhibition by expressing LKB1 ectopically in DU145 cells. In conclusion, our results demonstrated how AMPK controls the molecular mechanism underlying the differential biological functions of JNK, and they also provided a novel explanation for the antiapoptotic role of LKB1.
Yun
Hee
H
Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea.
Kim
Hak-Su
HS
Lee
Seshin
S
Kang
Insug
I
Kim
Sung Soo
SS
Choe
Wonchae
W
Ha
Joohun
J
D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004789:Enzyme Activation; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D017382:Reactive Oxygen Species; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase; D005947:Glucose