title: AMPK and PKA interaction in the regulation of survival of liver cancer cells subjected to glucose starvation.
abstract: The signaling pathways that govern survival response in hepatic cancer cells subjected to nutritional restriction have not been clarified yet. In this study we showed that liver cancer cells undergoing glucose deprivation both arrested in G0/G1 and died mainly by apoptosis. Treatment with the AMPK activator AICAR phenocopied the effect of glucose deprivation on cell survival, whereas AMPK silencing in HepG2/C3A, HuH-7 or SK-Hep-1 cells blocked the cell cycle arrest and the increase in apoptotic death induced by glucose starvation. Both AMPK and PKA were promptly activated after glucose withdrawal. PKA signaling had a dual role during glucose starvation: whereas it elicited an early decreased in cell viability, it later improved this parameter. We detected AMPK phosphorylation (AMPKα(Ser173)) by PKA, which was increased in glucose starved cells and was associated with diminution of AMPK activation. To better explore this inhibitory effect, we constructed a hepatocarcinoma derived cell line which stably expressed an AMPK mutant lacking that PKA phosphorylation site: AMPKα1(S173C). Expression of this mutant significantly decreased viability in cells undergoing glucose starvation. Furthermore, after 36 h of glucose deprivation, the index of AMPKα1(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.
authors.affiliation: Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
authors.forename: Anabela C
authors.initials: AC
authors.lastname: Ferretti
authors.affiliation: Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
authors.forename: Facundo M
authors.initials: FM
authors.lastname: Tonucci
authors.affiliation: Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
authors.forename: Florencia
authors.initials: F
authors.lastname: Hidalgo
authors.affiliation: Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
authors.forename: Evangelina
authors.initials: E
authors.lastname: Almada
authors.affiliation: Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Larocca
authors.affiliation: Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
authors.forename: Cristián
authors.initials: C
authors.lastname: Favre
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; apoptosis; cancer cell killing; hepatocellular carcinoma; signaling