Abstract LB-75: Glucocorticoid receptor activation inhibits p53-induced apoptosis of MCF10A myc cells via induction of protein kinase C epsilon

Abstract

Abstract Glucocorticoid receptor (GR) is a ligand dependent transcription factor that can promote apoptosis or survival in a cell specific manner. Activated GR has been reported to inhibit apoptosis in mammary epithelial cells (MECs) and breast cancer cells by increasing expression of pro-survival genes. In the current report, activated GR inhibited p53-dependent apoptosis in MCF10Amyc cells, immortalized MECs that are p53 wild-type and overexpress the MYC oncogene. Specifically, GR agonists hydrocortisone or dexamethasone (Dex) inhibited p53- dependent apoptosis induced in these cells by Cisplatin (Cis), ionizing radiation (IR), or the MDM2 antagonist Nutlin-3. In contrast, the GR antagonist RU486 sensitized the cells to apoptosis by these agents. Apoptosis inhibition was associated with maintenance of mitochondria membrane potential, diminished caspase 3 and 7 activation, and increased expression at both the mRNA and protein level of the antiapoptotic PKC family member, PKCepsilon (PKCε). Knockdown of PKCε via siRNA targeting reversed the protective effect of Dex and restored sensitivity to Cis, IR, and Nutlin-3 (Nutlin)-induced apoptosis. These data provide strong evidence that activated GR can inhibit p53-dependent apoptosis through induction of the anti-apoptotic factor PKCε. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-75. doi:1538-7445.AM2012-LB-75