Abstract LB-290: Glycogen synthase kinase-3β inhibits tumor growth and angiogenesis of gastric cancer

Abstract

Abstract Objective: The mechanisms underlying angiogenesis in cancer are diverse. Although in vitro studies have shown that glycogen synthase kinase-3β (GSK-3β) inhibits the expressions of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in several cancer cells, the implication of GSK-3β in cancer angiogenesis in vivo has not been shown. We examined the effects of GSK-3β on angiogenesis and human gastric cancer growth. Methods: Human gastric cancer cell lines SNU-638 and SNU-484 were stably transfected with either human wild-type (WT)-GSK-3β or kinase-dead (KD)-GSK-3β, and the effects of GSK-3β on tumor growth and angiogenesis were examined in in vivo experiments. Gastric cancer cells were injected into nude mice subcutaneously and the size of xenografted tumors was measured. The effects of GSK-3β inhibition on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, Western blotting and semiquantitative reverse transcription-polymerase chain reaction. In addition, GSK-3β effects on the HIF-1α degradation and synthesis were examined. Results: Xenografts in nude mice derived from stable gastric cell lines over-expressing KD-GSK-3β showed larger tumor volumes and higher microvessel density than those over-expressing WT-GSK-3β. Immunohistochemistry and Western blot analysis using xenografted tumor tissues showed that KD-GSK-3β over-expression increased immunoreactivity for Ki-67, HIF-1α, VEGF or CD31 compared with WT-GSK-3β over-expression. In addition, KD-GSK-3β over-expression enhanced HIF-1α expression under hypoxic conditions at the translational level, but not under normoxic conditions. Conclusion: These results indicate that GSK-3β inhibits gastric tumor growth and angiogenesis by regulating the expression of HIF-1α and VEGF in gastric cancer cells under hypoxic conditions. Our results suggest the potential usefulness of GSK-3β/HIF-1α/VEGF pathway to find molecular targets in gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2011-LB-290