Carcinogenesis Advance Access originally published online on November 26, 2008
Carcinogenesis 2009 30(3):529-537; doi:10.1093/carcin/bgn259
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AMP kinase signaling determines whether c-Jun N-terminal kinase promotes survival or apoptosis during glucose deprivation
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 130-701, Korea
* To whom correspondence should be addressed. Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, #1, Hoegi-dong, Dongdaemoon-gu, Seoul 130-701, Korea. Tel: +82 2 961 0940; Fax: +82 2 959 8168; Email: wchoe{at}khu.ac.kr
Correspondence may also be addressed to Joohun Ha. Tel: +82 2 961 0921; Fax: +82 2 959 8168;Email: hajh{at}khu.ac.kr
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.
Abbreviations: AMP, adenosine monophosphate; AMPK, adenosine monophosphate-activated protein kinase; ATP, adenosine triphosphate; CA, constitutive active; DN, dominant negative; GFP, green fluorescent protein; GPx, glutathione peroxidase; JNK, c-Jun N-terminal kinase; MEF, mouse embryonic fibroblast; MKK4, mitogen-activated protein kinase kinase 4; MKP, mitogen-activated protein kinase phosphatase; NAC, N-acetyl-L-cysteine; PBS, phosphate-buffered saline; ROS, reactive oxygen species; SEK1, stress-activated protein kinase kinase 1; WT, wild-type
Received May 30, 2008; revised October 9, 2008; accepted November 1, 2008.