Roles of protein kinase C in cell death and breast cancer

Abstract: Aberrant protein kinase C (PKC) activity and expression is implicated in different malignancies. To study the role of different PKC isoforms in breast cancer the expression of PCKα, δ and ε was evaluated in breast cancer tumors. In addition the effect of siRNA-mediated knockdown of the isoforms was studied in a global gene expression analysis. We found that high PKCα levels correlate with poor prognosis, high proliferation and estrogen receptor negativity. We have also seen that PKCα suppresses the expression of stanniocalcin-1 in breast cancer cells. Previous reports have shown that PKCδ is a survival factor in several breast cancer cells. Here we show that Smac, a proapoptotic protein, associates with PKCδ in many different cancer cell lines. Furthermore, the PKCδ-Smac association was dissociated upon paclitaxel treatment. Upon PKC activation with TPA the PKCδ-Smac complex was stabilized and the paclitaxel-mediated dissociation and death was suppressed. The decreased cell death could potentially be caused by a competition between PKCδ and XIAP for Smac binding. We also show that activation of PKC sensitizes some breast cancer cell lines to a Smac mimetic called LBW242, a small molecule that mimic the effect of Smac. We found that the TPA+LBW242-mediated cell death was dependent on TPA-induced TNFα production. In addition the combination of TPA+LBW242 enables complex II formation and caspase-3 cleavage, a probable cause of the concomitant cell death observed.