Abstract 2064: GSK3 regulation of Mcl1 and beta catenin involves I kappa B alpha

Abstract

Abstract Recently we demonstrated that the gene NFKBIA is deleted in most of the nonclassic sub types of Glioma. We have also shown that the over-expression of NFKBIA causes sensitization of the cancer cells towards various chemotherapeutic agents. We further extended our study to investigate the mechanism behind this chemo-sensitization by using temazolamide and and BAY 11-7082. We used two glioma cell lines U251, LN229 and one breast cancer cell line MDAMB231. Very interestingly we found that over expression of NFKBIA itself results in the down regulation of two major anti apoptotic proteins Mcl1 and Bcl-XL respectively. Next we treated the cells with Temozolamide and BAY 11-7082 separately and analysed the protein profile by western blotting. We have seen a strong down regulation of Mcl1 in all the cell lines and BCL-xl in two cell lines. But we didn't see any difference in the abundance of another related anti apoptotic protein Bcl2. We have seen enhanced apoptotic signal corresponding with the Mcl1 degradation. So it is clear from the study that the down regulation of Mcl1 by NFKBIA makes cells more susceptible towards the chemotherapeutic drugs. Interestingly we also found that the protein beta-catetnine, a major component of a Wnt signaling pathway, is up regulated with the IκBα over expression and remain unchanged with the chemotherapeutic drugs in all the cell lines. Mcl1 degradation was mediated by the phosphorylation of GSK3 and the phosphorylated GSK3 prevent the usual proteasomal degradation of the beta-catetnine leading to it's accumulation in the cell. Thus we can conclude that NFKBIA paly an important role in the phosphorylation of GSK3 and results in the regulation of Mcl-1 and beta catenine. Citation Format: Vineshkumar Thidil Puliyappadamba, Nanda Kumar Thudi, Markus Bredel. GSK3 regulation of Mcl1 and beta catenin involves I kappa B alpha. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2064. doi:10.1158/1538-7445.AM2015-2064