Loss of PKC delta Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/beta-Catenin Pathway and Mcl-1 Accumulation

摘要

Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKC delta silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis. In prostate cancer cells, PKC delta seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/beta-catenin pathway. PKC delta silencing induces activation of Wnt/beta-catenin pathway and the expression of its target genes, including Aurora kinase A, which is involved in activation of Akt and both factors play a key role in GSK3 beta inactivation and consequently in the stabilization of beta-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/beta-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKC delta. Finally, we observe that high Gleason score prostate tumors lose PKC delta expression and this correlates with higher activation of beta-catenin, inactivation of GSK3 beta, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/beta-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKC delta expression. (C) 2016 AACR.