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

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Date

2016

Authors

Flores, M Luz
Castilla, Carolina
Gasca, Jessica
Medina, Rafael
Perez-Valderrama, Begoña
Romero, Francisco
Japon, Miguel A
Saez, Carmen

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American Association for Cancer Research
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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 PKCδ 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, PKCδ seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/β-catenin pathway. PKCδ silencing induces activation of Wnt/β-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 GSK3β inactivation and consequently in the stabilization of β-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/β-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCδ. Finally, we observe that high Gleason score prostate tumors lose PKCδ expression and this correlates with higher activation of β-catenin, inactivation of GSK3β, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/β-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCδ expression. Mol Cancer Ther; 15(7); 1713-25. ©2016 AACR.

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MeSH Terms

Apoptosis
Aurora Kinase A
Cell Line, Tumor
Chromones
Drug Resistance, Neoplasm
Gene Expression
Humans
Male
Mitosis
Morpholines
Myeloid Cell Leukemia Sequence 1 Protein
Paclitaxel
Prostatic Neoplasms
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-bcl-2
Wnt Signaling Pathway
beta Catenin

DeCS Terms

Neoplasias de la próstata
Paclitaxel
Quimioterapia
Clasificación del tumor
Eficacia

CIE Terms

Keywords

Antineoplastic Agents, Phytogenic, Cell Cycle Checkpoints, Gene Silencing, Models, Biological, Protein Kinase C-delta

Citation

Flores ML, Castilla C, Gasca J, Medina R, Pérez-Valderrama B, Romero F, et al. Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation. Mol Cancer Ther. 2016 Jul;15(7):1713-25.