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.
AMPK is a serine/threonine protein kinase family and we recently identified a novel member, ARK5. The activation of ARK5 is triggered by Akt, and ARK5 induces tumor cell survival during nutrient starvation. In the current study, we investigated the mechanisms of induction of cell survival by ARK5. Human hepatoma HepG2 cells undergo necrotic cell death within 24 h after the start of glucose starvation, and the cell death signaling has been found to be mediated by death-receptor-independent activation of caspase 8. When HepG2 cells were transfected with ARK5 expression vector and subjected to several cell death stimuli, ARK5 was found to suppress cell death by glucose starvation, TRAIL, and TNF-alpha, but not by ultraviolet irradiation, camptothecin, or doxorubicin. Western blotting analysis revealed that both TRAIL and glucose starvation induced Bid cleavage and FLIP degradation following caspase 8 activation in a time-dependent manner, and ARK5 overexpression clearly delayed Bid cleavage, FLIP degradation, and caspase 8 activation. On the basis of the results of this study, we report that cell survival induced by ARK5 is, at least in part, due to inhibition of caspase 8 activation.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D002470:Cell Survival; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008113:Liver Neoplasms / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009336:Necrosis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012097:Repressor Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; C470845:NUAK1 protein, human; D005947:Glucose