Mol Cell

Mol Cell. Expression of this mutant significantly decreased viability in cells undergoing glucose starvation. Furthermore, after 36 h of glucose deprivation, the index of AMPK1(S173C) apoptotic cells doubled the apoptotic index observed in control cells. Two main remarks arise: 1. AMPK is the central signaling kinase in the scenario of cell cycle arrest and death induced by glucose starvation in hepatic cancer cells; 2. PKA phosphorylation of Ser173 comes out as a strong control point that limits the antitumor effects of AMPK in this situation. < 0.05 was considered statistically significant. Acknowledgments Authors especially thank Mara Ojeda at IFISE-CONICET for her expert technical support in performing cytometric assays, and Dr. Dietbert Neumann at Maastricht University for his generous gift of AMPK1 plasmids. Abbreviations HCChepatocellular carcinomaAMPKAMP activated kinasePKAcAMP-protein kinase AAICAR5-Aminoimidazole-4-carboxamide ribonucleotidedbcAMPdibutyryl-cAMPPIpropidium iodidesiRNAsmall interfering RNAKDknock downROSradical oxygen speciesWTwild typePumap53-upregulated modulator of apoptosisDMEMDulbecco modified Eagle medium Footnotes CONFLICTS OF INTEREST The authors declare no conflict of interest. FINANCIAL SUPPORT This work was supported by the Argentinean Government through ANPCyT (PICT-2012 #1362) and CONICET (PIP #11220120100287CO) grants. REFERENCES 1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Dot1L-IN-1 Zeuzem S, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378C390. [PubMed] [Google Scholar] 2. Zhu AX. Molecularly targeted therapy for advanced hepatocellular carcinoma in. 2012: current status and future perspectives. Semin Oncol. 2012;39:493C502. [PubMed] [Google Scholar] 3. Iyer VV, Yang H, Ierapetritou MG, Roth CM. Effects of glucose and insulin on HepG2-C3A cell Dot1L-IN-1 metabolism. Biotechnol Bioeng. 2010;107:347C356. [PubMed] [Google Scholar] 4. FGFR4 Chang SH, Garcia J, Melendez JA, Kilberg MS, Agarwal A. Heme oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain. Biochem J. 2003;371:877C885. [PMC free article] [PubMed] [Google Scholar] 5. Lee HG, Li MH, Joung EJ, Na HK, Cha YN, Surh YJ. Nrf2-Mediated heme oxygenase-1 upregulation as adaptive survival response to glucose deprivation-induced apoptosis in HepG2 cells. Antioxid Redox Signal. 2010;13:1639C1648. [PubMed] [Google Scholar] 6. Suzuki A, Kusakai GK, Kishimoto A, Lu J, Ogura T, Esumi H. ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation. Oncogene. 2003;22:6177C6182. [PubMed] [Google Scholar] 7. Ferretti AC, Mattaloni SM, Ochoa JE, Larocca MC, Favre C. Protein kinase A signals apoptotic activation in glucose-deprived hepatocytes: participation of reactive oxygen species. Apoptosis. 2012;17:475C91. [PubMed] [Google Scholar] 8. Leadsham JE, Gourlay CW. cAMP/PKA signaling balances respiratory activity with mitochondria dependent apoptosis via Dot1L-IN-1 transcriptional regulation. BMC Cell Biol. 2010;11:92. [PMC free article] [PubMed] [Google Scholar] 9. Lee J, Choi YH, Nguyen PM, Kim J-S, Jae LS, Trepel JB. Cyclic AMP induces inhibition of cyclin A expression and growth arrest in human hepatoma cells. Biochim Biophys Acta. 1999;1449:261C268. [PubMed] [Google Scholar] 10. Dot1L-IN-1 Ko FC, Chan LK, Sze KM, Yeung YS, Tse EY, Lu P, Yu MH, Ng IO, Yam JW. PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis. Nat Commun. 2013;4:1618. [PubMed] [Google Scholar] 11. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251C62. [PMC free article] [PubMed] [Google Scholar] 12. Imamura K, Ogura T, Kishimoto A, Kaminishi M, Esumi H. Cell cycle regulation via p53 phosphorylation by a 5-AMP activated protein.