title: AMPK interacts with β-catenin in the regulation of hepatocellular carcinoma cell proliferation and survival with selenium treatment.
abstract: Selenium has received much attention as an anticancer agent, although the mechanisms of action underlying its pro-apoptotic properties remain unclear. Tumors that respond well to antioxidant treatments, such as hepatocellular carcinoma (HCC), may benefit from treatment with selenium as this compound also has antioxidant properties. Furthermore, a major oncogenic driver in HCC is the nuclear transcription co-activator, β-catenin. In the present study, we examined the mechanism by which selenium reduces survival of HCC cells, and whether this was associated with modulation of the β-catenin pathway. Hep3B cell lines and cancer cell xenografted animals were treated with selenium, and apoptotic events or signals such as AMPK, β-catenin and GSK3β were determined. Further interactions among β-catenin, glycogen synthase kinase 3β (GSK3β), and AMPK were explored by applying AMPK small interfering RNA (siRNA) or GSK3β siRNA with western blotting or immunofluorescence microscopic observation. Selenium activated AMPK, which in turn suppressed β-catenin. Selenium induced the translocation of AMPK into the nucleus and prevented the accumulation of β-catenin therein. Upon inactivation of AMPK by AMPK siRNA, selenium no longer modulated β-catenin, implying that AMPK is an upstream signal for β-catenin. We found that the binding between AMPK and β-catenin occurs in the cytosolic fraction, and therefore concluded that the cancer cell antiproliferative effects of selenium are mediated by a GSK3β-independent AMPK/β-catenin pathway, although AMPK-mediated GSK3β regulation was also observed. We primarily discovered that AMPK is a crucial regulator initiating selenium-induced inhibition of β-catenin expression. Taken together, these novel findings help to illuminate the molecular mechanisms underlying the anticancer effect of selenium and highlight the regulation of β-catenin by selenium.
authors.affiliation: Department of Biological Sciences and Biotechnology, Hannam University Daedeok Valley Campus, Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Yun-Kyoung
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences and Biotechnology, Hannam University Daedeok Valley Campus, Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Food and Nutrition, Hannam University Daedeok Valley Campus, Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Ock Jin
authors.initials: OJ
authors.lastname: Park
authors.affiliation: Department of Biological Sciences and Biotechnology, Hannam University Daedeok Valley Campus, Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003600:Cytosol; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D011485:Protein Binding; D034741:RNA, Small Interfering; D012643:Selenium / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D012643:Selenium