TY - JOUR T1 - Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK651 JF - Proc.Natl.Acad.Sci.U.S.A Y1 - 2014 A1 - Liu,X. A1 - Chhipa,R.R. A1 - Pooya,S. A1 - Wortman,M. A1 - Yachyshin,S. A1 - Chow,L.M. A1 - Kumar,A. A1 - Zhou,X. A1 - Sun,Y. A1 - Quinn,B. A1 - McPherson,C. A1 - Warnick,R.E. A1 - Kendler,A. A1 - Giri,S. A1 - J Poels A1 - K. Norga A1 - Viollet,B. A1 - Grabowski,G.A. A1 - Dasgupta,B. KW - a KW - Activation KW - Activity KW - Agent KW - Agents KW - agonists KW - an KW - Animals KW - article KW - AS KW - association KW - Biology KW - Brain Neoplasms KW - cancer KW - Cell KW - Cell Cycle KW - Cell Proliferation KW - cells KW - Cells,Cultured KW - CHILDREN KW - Clinical KW - clinical trial KW - Clinical trials KW - drug effects KW - effect KW - electronic KW - enzymology KW - function KW - functions KW - Genetic KW - genetics KW - Glioblastoma KW - growth KW - Hand KW - Hematology KW - hospital KW - Human KW - Humans KW - im KW - in vivo KW - IS KW - IT KW - journal KW - Lipogenesis KW - mechanism KW - mechanisms KW - medical KW - metabolism KW - Metformin KW - mice KW - Mice,Knockout KW - ON KW - oncology KW - pathology KW - pharmacology KW - physiology KW - protein KW - Protein Kinases KW - regulation KW - Research KW - Research Support KW - response KW - result KW - results KW - Role KW - SB - IM KW - stress KW - survival KW - Target KW - Tissue KW - TOR Serine-Threonine Kinases KW - tumor KW - viability AB - The multifunctional AMPK-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that plays an important role in cell proliferation, growth, and survival. It remains unclear whether AMPK functions as a tumor suppressor or a contextual oncogene. This is because although on one hand active AMPK inhibits mammalian target of rapamycin (mTOR) and lipogenesis--two crucial arms of cancer growth--AMPK also ensures viability by metabolic reprogramming in cancer cells. AMPK activation by two indirect AMPK agonists AICAR and metformin (now in over 50 clinical trials on cancer) has been correlated with reduced cancer cell proliferation and viability. Surprisingly, we found that compared with normal tissue, AMPK is constitutively activated in both human and mouse gliomas. Therefore, we questioned whether the antiproliferative actions of AICAR and metformin are AMPK independent. Both AMPK agonists inhibited proliferation, but through unique AMPK-independent mechanisms and both reduced tumor growth in vivo independent of AMPK. Importantly, A769662, a direct AMPK activator, had no effect on proliferation, uncoupling high AMPK activity from inhibition of proliferation. Metformin directly inhibited mTOR by enhancing PRAS40's association with RAPTOR, whereas AICAR blocked the cell cycle through proteasomal degradation of the G2M phosphatase cdc25c. Together, our results suggest that although AICAR and metformin are potent AMPK-independent antiproliferative agents, physiological AMPK activation in glioma may be a response mechanism to metabolic stress and anticancer agents VL - 111 CP - 4 U1 - 651 M3 - 1311121111 [pii];10.1073/pnas.1311121111 [doi] ER -