PKCδ protects human breast tumor MCF-7 cells against tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a number of tumorogenic or transformed cells, yet is relatively non-toxic to most normal cells, therefore, it is a promising agent for cancer therapy. However, some cancer cell lines were resistant to TRAIL cytoxicity, including MCF-7 breast cancer cells. The mechanism is not clear. Here, we report that protein kinase C delta (PKCδ) protects MCF-7 cells from the recombinant soluble TRAIL (rsTRAIL)- mediated apoptosis. It was demonstrated that rottlerin, a PKCδ inhibitor, sensitized MCF-7 cells to rsTRAIL cytoxicity. Combination of rottlerin and rsTRAIL inhibited PKCδ translocation from the cytosol to membrane, and PKCδ kinase activity on the cell membrane was kept pace with the change of PKCδ expression. Moreover, inhibition of PKCδ by interference RNA could facilitate apoptosis of MCF-7 cells induced by rsTRAIL. Further experiments on the signal machinery showed that rottlerin increased the sensitivity of MCF-7 cells to rsTRAIL by suppressing the transcription activity of NF-κB, and enhancing the caspase-processing to generate executive apoptotic signals. These findings indicate that PKCδ functions as a survival factor protecting MCF-7 cells from the apoptosis induced by rsTRAIL. © 2005 Wiley-Liss, Inc.