Glucocorticoid Receptor Activation Inhibits p53-induced Apoptosis of MCF10Amyc Cells via Induction of Protein Kinase Cϵ

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 pro-survival gene expression. In the current report, activated GR inhibited p53-dependent apoptosis in MCF10A cells and human mammary epithelial cells (HMECs) that overexpress the MYC oncogene. Specifically, GR agonists hydrocortisone or dexamethasone (Dex) inhibited p53-dependent apoptosis induced 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 anti-apoptotic PKC family member, PKC-epsilon (PKCe). Knockdown of PKCe via siRNA targeting reversed the protective effect of Dex and restored apoptosis sensitivity. These data provide evidence that activated GR can inhibit p53-dependent apoptosis through induction of the anti-apoptotic factor PKCe.