title: 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 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.
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain.
authors.forename: M Luz
authors.initials: ML
authors.lastname: Flores
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Castilla
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gasca
authors.affiliation: Department of Urology, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Medina
authors.affiliation: Department of Oncology, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Pérez-Valderrama
authors.affiliation: Department of Microbiology, Faculty of Biology, Universidad de Sevilla, Seville, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Romero
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain. Department of Pathology, Hospital Universitario Virgen del Rocío, Seville, Spain. csaez1@us.es mjapon@cica.es.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Japón
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain. Department of Pathology, Hospital Universitario Virgen del Rocío, Seville, Spain. csaez1@us.es mjapon@cica.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sáez
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000172:deficiency*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051176:beta Catenin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D064096:Aurora Kinase A; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D017239:Paclitaxel