Hypoxic inactivation of glycogen synthase kinase-3β promotes gastric tumor growth and angiogenesis by facilitating hypoxia-inducible factor-1 signaling

• Published in: APMIS : acta pathologica, microbiologica et immunologica Scandinavica microbiologica et immunologica Scandinavica, 2016-09, Vol.124 (9), p.748-756
• Main Authors: Ko, Young San, Cho, Sung Jin, Park, Jinju, Choi, Yiseul, Lee, Jae-Seon, Youn, Hong-Duk, Kim, Woo Ho, Kim, Min A, Park, Jong-Wan, Lee, Byung Lan
• Format: Article
• Language: English
• Subjects: angiogenesis; Animals; Blotting, Western; Cell Line, Tumor; Cell Survival; Disease Models, Animal; gastric cancer; Glycogen Synthase Kinase 3 beta - metabolism; Glycogen synthase kinase-3β; Heterografts; HIF-1α; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunohistochemistry; Male; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Signal Transduction; Stomach Neoplasms - pathology; Stomach Neoplasms - physiopathology
• ISSN: 0903-4641; 1600-0463
• DOI: 10.1111/apm.12569

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.