Abstract 4149: A newly developed GSK-3 inhibitor, CG9, inhibits breast cancer cell proliferation through estrogen receptor α degradation

Abstract

Abstract GSK-3 (glycogen synthase kinase-3) has a major role in Wnt and Hedgehog signaling pathways and regulates the cell cycle, stem cell renewal and differentiation, apoptosis, and insulin action. The pharmacological inhibitors of GSK-3 could be used to treat several diseases, including Alzheimer's disease, other neurodegenerative diseases and diabetes. In this study, we investigated the cellular and molecular effects of a newly developed GSK-3 inhibitor, CG9, in seven breast cancer cell lines of the NCI-60 cell line panel. CG9 treatment increased inhibitory phosphorylation of GSK-3α/β (Ser21/9), whereas decreased activating phosphorylation of GSK-3β (Tyr216), together with the overall reduction of the level of GSK-3 proteins. CG9 also induced growth inhibition and stimulated a caspase-dependent apoptotic pathway regardless of estrogen receptor (ER) positivity with IC50 of 12 μM in T47D to ≤ 0.1 μM in MCF7 cells. The GSK inhibitor down-regulated the cellular levels of ERα and cyclin D in ERα-positive MCF7 cells. Immunoprecipitation experiments showed that CG9 treatment inhibits the interaction of Hsp90 with ERα in cytoplasm. Taken together these results indicate that CG9 may be an effective anti-cancer agent in human breast cancers. Currently, we are investigating the efficiency of CG9 compared with that of antiestrogen tamoxifen (Tam) and a possibility of combined treatment with CG9 and Tam. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4149.