Differential effects of protein kinase C-eta on apoptosis versus senescence

Protein kinase C-eta (PKC eta) is considered an anti-apoptotic kinase, which promotes cell survival and chemoresistance in several cancers, including breast cancer. We have recently shown that PKC eta positively regulates the anti-apoptotic protein Mcl-1 in breast cancer cells, and depletion of PKC eta induced proteasomal degradation of Mcl-1. We therefore examined if depletion of PKC eta would enhance cellular sensitivity to chemotherapeutic agents. Silencing of PKC eta by siRNA attenuated apoptosis induced by doxorubicin and paclitaxel in both MCF-7 and T47D breast cancer cells. While silencing of Mcl-1 caused a substantial increase in apoptosis induced by doxorubicin, the combined knockdown of PKC eta and Mcl-1 was less effective. Depletion of PKC eta also caused an increase in the abundance of the cell cycle inhibitor p27 and a decrease in the clonogenic survival of MCF-7 and T47D cells. PKC eta knockdown was associated with an increase in senescence-associated beta-galactosidase (SA-beta-gal) activity but this increase was attenuated by knockdown of p27. The suppression of doxorubicin-induced apoptosis by PKC eta knockdown was partially relieved when p27 was depleted. Since loss of proliferative capacity during senescence could cause resistance to chemotherapeutic drugs, our results suggest that PKC eta knockdown inhibits apoptosis by inducing p27-mediated senescence.