title: Hypoxic inactivation of glycogen synthase kinase-3β promotes gastric tumor growth and angiogenesis by facilitating hypoxia-inducible factor-1 signaling.
abstract: Since the molecular mechanism of hypoxic adaptation in cancer cells is cell-type specific, we investigated whether glycogen synthase kinase-3β (GSK-3β) activation is involved in hypoxia-induced gastric tumor promotion. Stable gastric cancer cell lines (SNU-638, SNU-484, MKN1, and MKN45) were cultured under hypoxic conditions. Cells overexpressing wild-type GSK-3β (WT-GSK-3β) or kinase-dead mutant of GSK-3β (KD-GSK-3β) were generated and used for cell culture and animal studies. In cell culture experiments, hypoxia decreased GSK-3β activation in gastric cancer cells. Cell viability and the expressions of HIF-1α protein and VEGF mRNA in gastric cancer cells were higher in KD-GSK-3β transfectants than in WT-GSK-3β transfectants under hypoxic conditions, but not under normoxic conditions. Gastric cancer xenografts showed that tumor growth, microvessel area, HIF-1α activation, and VEGF expression were higher in KD-GSK-3β tumors than in WT-GSK-3β tumors in vivo. In addition, the expression of hypoxia-induced HIF-1α protein was regulated by GSK-3β at the translational level. Our data suggest that GSK-3β is involved in hypoxic adaptation of gastric cancer cells as an inhibitory upstream regulator of the HIF-1α/VEGF signaling pathway.
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Young San
authors.initials: YS
authors.lastname: Ko
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Cho
authors.affiliation: Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jinju
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yiseul
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, South Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Hong-Duk
authors.initials: HD
authors.lastname: Youn
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Min A
authors.initials: MA
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea.|Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea.|Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.|Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Byung Lan
authors.initials: BL
authors.lastname: Lee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology* / Q000503:physiopathology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Glycogen synthase kinase-3β; HIF-1α; angiogenesis; gastric cancer; hypoxia