Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

Abstract

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 PKCd 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, PKCd seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/b-catenin pathway. PKCd silencing induces activation of Wnt/b-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 GSK3b inactivation and consequently in the stabilization of b-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/b-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCd. Finally, we observe that high Gleason score prostate tumors lose PKCd expression and this correlates with higher activation of b-catenin, inactivation of GSK3b, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/b-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCd expression.

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression

“…It is well documented that constitutive activation of β-catenin signaling pathway plays a major role in cancer progression and metastasis (3,24) and drug resistance (42). Accumulating evidences also suggest that β-catenin cross-talks with other oncogenic signaling components leading to more aggressive phenotype of PrCa cells (43).…”

Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells

“…Elucidation of the mechanisms of paclitaxel resistance may help to identify biomarkers for the development of alternative or sensitizing therapies. We previously showed that Mcl-1 is a determinant of the response to paclitaxel treatment, is overexpressed in many paclitaxel-resistant tumors, and that downregulation of Mcl-1 restores the sensitivity to paclitaxel [6,7,8]. Herein, we show that Mcl-1 is downregulated in sensitive 5637 cells, but not in resistant HT1197 cells in response to paclitaxel and that Mcl-1 is overexpressed in many muscle-invasive bladder carcinomas.…”

“…Anti-apoptotic proteins may also be involved in taxane resistance. We have previously shown that anti-apoptotic Mcl-1 is related to paclitaxel resistance in prostate and breast cancer and that Mcl-1 over-expression is a frequent event in aggressive cancers [6,7,8].…”

lncRNA GAS5 enhances tumor stem cell-like medicated sensitivity of paclitaxel and inhibits epithelial-to-mesenchymal transition by targeting miR-18a-5p/STK4 pathway in prostate cancer

“…Paclitaxel, as a microtubule-targeting chemotherapeutic drug, can be used for clinical treatment of PCA. However, the paclitaxel chemoresistance often occurs during the process of treatment and seriously affects prognosis of the patients [43,44]. Increasing evidence have shown that lncRNAs play vital roles in progression of cancer regulation and chemotherapy resistance [20,35,45].…”