Abstract 4131: Activation of PKC-delta inhibits apoptosis leading to mitomycin C resistance

Abstract

Abstract Antioxidant-induced protein kinase C delta (PKCdelta) is known to phosphorylate cell survival transcription factor Nrf2. Phosphorylated Nrf2 translocates to the nucleus leading to coordinated activation of detoxifying enzyme gene expression. This mechanism is critical for protection against chemical and radiation stress and cell survival. Human breast cancer MCF-7 cells expressing endogenous PKCdelta, human breast cancer BT549 cells deficient in PKCdelta expression (PKCdelta-null) and BT549-C1 cells expressing cDNA derived PKCdelta demonstrated differential survival and apoptotic death responses to anti-tumor drug mitomycin C. MCF-7 and BT549-C1 cells expressing PKCdelta showed increased survival and decreased apoptotic cell death as compared with PKCdelta-null BT549 cells. The studies also demonstrated that mitomycin C induced serine40 phosphorylation and nuclear translocation of Nrf2. Further studies determined that Nrf2 translocation in the nucleus led to an increase in Bcl2 and BclXL expression that contributed to the inhibition of apoptosis, increased cell survival and mitomycin C resistance. Interestingly, inclusion of antioxidant tert-butyl hydroquinone with mitomycin C further enhanced the PKCdelta effect on cell survival and apoptotic cell death. These results led to the conclusion that PKCdelta is endogenous factor in drug resistance and could serve as a therapeutic target. 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 4131.