PKCε induces Bcl-2 by activating CREB

Protein kinase C epsilon (PKC epsilon ) is a transforming oncogene and an important anti-apoptotic protein. We previously demonstrated that overexpression of PKC epsilon in MCF-7 breast cancer cells caused an increase in anti-apoptotic Bcl-2 and a decrease in pro-apoptotic Bid, attenuating tumor necrosis factor- alpha (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The objective of our present study was to determine the mode of induction of Bcl-2 by PKC epsilon in breast cancer cells. siRNA silencing of either PKC epsilon or Akt in MCF-7 cells, which overexpress Akt, decreased Bcl-2 protein and mRNA levels. However, knockdown of PKC epsilon , but not Akt, led to the decrease in Bcl-2 at both protein and mRNA levels in MDA-MB-231 breast cancer cells, which overexpress PKC epsilon but contain little constitutively-active Akt. Knockdown of PKC epsilon decreased phosphorylation of cAMP response element-binding protein (CREB) at Ser133 in MDA-MB-231 cells, and depletion of CREB by siRNA decreased Bcl-2 at both the protein and mRNA levels. In addition, knockdown of CREB sensitized MDA-MB-231 cells to TRAIL-mediated cell death. These results suggest that PKC epsilon regulates Bcl-2 induction through activation of the transcription factor CREB.