title: Activation of AMP-activated protein kinase is involved in vincristine-induced cell apoptosis in B16 melanoma cell.
abstract: The molecular basis for induction of apoptosis in melanoma cells by vincristine remains unknown. Here we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found for the first time that vincristine induces AMPK activation (AMPKα, Thr 172) and Acetyl-CoA carboxylase (ACC, Ser 79) (a downstream molecular target of AMPK) phosphorylation in cultured melanoma cells in vitro. Reactive oxygen species (ROS) dependent LKB1 activation serves as the upstream signal for AMPK activation. AMPK inhibitor (compound C) or AMPKα siRNA knockdown inhibits vincristine induced B16 melanoma cell apoptosis, while AMPK activator 5-aminoimidazole-4-carboxamide-1-β-riboside (AICAR) enhances it. AMPK activation is involved in vincristine induced p53 phosphorylation and stabilization, the latter is known to mediate melanoma cell apoptosis. Further, activation of AMPK by vincristine inhibits mTOR Complex 1 (mTORC1) in B16 melanoma cells, which serves as another important mechanism to induce melanoma cell apoptosis. Our study provides new insights into understanding the cellular and molecular mechanisms of vincristine induced cancer cell death/apoptosis. We suggest that combining AMPK activator AICAR with vincristine may have potential to be used as a new therapeutic intervention against melanoma.
authors.affiliation: Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu Province, China.
authors.forename: Min-Bin
authors.initials: MB
authors.lastname: Chen
authors.forename: Wen-Xiang
authors.initials: WX
authors.lastname: Shen
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: Wu
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Gu
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D046912:Multiprotein Complexes; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020536:Enzyme Activators; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D016159:Tumor Suppressor Protein p53; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D014750:Vincristine; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide