title: Critical Role of AMPK/FoxO3A Axis in Globular Adiponectin-Induced Cell Cycle Arrest and Apoptosis in Cancer Cells.
abstract: Adiponectin predominantly secreted from adipose tissue has exhibited potent anti-proliferative properties in cancer cells via modulating cell cycle and apoptosis. FoxO3A, a Forkhead box O member of the transcription factor, plays a critical role in modulating expression of genes involved in cell death and/or survival. In this study, we investigated the role of FoxO3A signaling in anti-cancer activities of adiponectin. Herein, we have shown that treatment with globular adiponectin (gAcrp) increases p27 but decreases cyclinD1 expression in human hepatoma (HepG2) and breast (MCF-7) cancer cells. Gene ablation of FoxO3A prevented gAcrp-induced increase in p27 and decreased in cyclin D1 expression, and further ameliorated cell cycle arrest by gAcrp, indicating a critical role of FoxO3A in gAcrp-induced cell cycle arrest of cancer cells. Moreover, treatment with gAcrp also induced caspase-3/7 activation and increased Fas ligand (FasL) expression in both HepG2 and MCF-7 cells. Transfection with FoxO3A siRNA inhibited gAcrp-induced caspase-3/7 activation and FasL expression, suggesting that FoxO3A signaling also plays an important role in gAcrp-induced apoptosis of cancer cells. We also found that gene silencing of AMPK prevented gAcrp-induced nuclear translocation of FoxO3A in HepG2 and MCF-7 cells. In addition, suppression of AMPK also blocked gAcrp-induced cell cycle arrest and further attenuated gAcrp-induced caspase-3/7 activation, indicating that AMPK signaling plays a pivotal role in both gAcrp-induced cell cycle arrest and apoptosis via acting as an upstream signaling of FoxO3A. Taken together, our findings demonstrated that AMPK/FoxO3A axis plays a cardinal role in anti-proliferative effect of adiponectin in cancer cells.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Anup
authors.initials: A
authors.lastname: Shrestha
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Saroj
authors.initials: S
authors.lastname: Nepal
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Keimyung University, Daegu, Republic of Korea.
authors.forename: Gil-Saeng
authors.initials: GS
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Keimyung University, Daegu, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Gyu Hwan
authors.initials: GH
authors.lastname: Park
authors.affiliation: Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute, Daejeon, Republic of Korea.
authors.forename: Sunghee
authors.initials: S
authors.lastname: Jung
authors.affiliation: Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute, Daejeon, Republic of Korea.
authors.forename: Jaecheong
authors.initials: J
authors.lastname: Lim
authors.affiliation: Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute, Daejeon, Republic of Korea.
authors.forename: Eunha
authors.initials: E
authors.lastname: Cho
authors.affiliation: Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute, Daejeon, Republic of Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000502:physiology; D053222:Fas Ligand Protein / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C505661:FASLG protein, human; C499517:FOXO3 protein, human; D053222:Fas Ligand Protein; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7