Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Abstract

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-kB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. Mol Cancer Ther; 13(5); 1270-84. Ó2014 AACR.

HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer

“…The former suggests that there is a fraction of chemoresistant cells in the tumor mass, which initiates tumorigenesis after chemotherapy; the latter emphasizes that the ability of chemoresistance is induced by chemodrugs, manifesting an inevitable result for chemotherapy. Mechanistically, chemoresistance can be ascribed to various reasons including drug inactivation, off-target, cell death inhibition, epigenetics, decreased drug uptake/ increased drug efflux and EMT (30,31). The drug efflux system attracts more and more attentions for its irreplaceable roles in chemoresistance, which is mainly mediated by ABC superfamily.…”

INPP4B reverses docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer

“…It is reported that Dox-resistant PCa cells could express EMT markers and EMT could reverse Dox resistance [15], thus we explored the role of INPP4B in Dox-induced EMT in the study. The results demonstrated that overexpression of INPP4B significantly downregulated the mesenchymal markers fibronectin (Fig.…”

A comprehensive review of genomic landscape, biomarkers and treatment sequencing in castration-resistant prostate cancer

“…Activation of the EMT program is characterized by the loss of E-cadherin and the gain of mesenchymal markers such as Vimentin and N-cadherin, which increases the migratory ability of the cells and contribute notably to the interaction of tumors cells with the microenvironment at the bone [24][25][26]. Such a phenomenon leads to the activation of a set of transcription factors including Twist and Snail, and is orchestrated by epigenetic remodeling involving the Polycomb complex [27].…”