Acquisition of paclitaxel resistance is associated with a more aggressive and invasive phenotype in prostate cancer

Abstract

Drug resistance is a major limitation to the successful treatment of advanced prostate cancer (PCa). Patients who have metastatic, castration-resistant PCa (mCRPC) are treated with chemotherapeutics. However, these standard therapy modalities culminate in the development of resistance. We established paclitaxel resistance in a classic, androgen-insensitive mCRPC cell line (DU145) and, using a suite of molecular and biophysical methods, characterized the structural and functional changes in vitro and in vivo that are associated with the development of drug resistance. After acquiring paclitaxel-resistance, cells exhibited an abnormal nuclear morphology with extensive chromosomal content, an increase in stiffness, and faster cytoskeletal remodeling dynamics. Compared with the parental DU145, paclitaxel-resistant (DU145-TxR) cells became highly invasive and motile in vitro, exercised greater cell traction forces, and formed larger and rapidly growing tumors in mouse xenografts. Furthermore, DU145-TxR cells showed a discrete loss of keratins but a distinct gain of ZEB1, Vimentin and Snail, suggesting an epithelial-to-mesenchymal transition. These findings demonstrate, for the first time, that paclitaxel resistance in PCa is associated with a trans-differentiation of epithelial cell machinery that enables more aggressive and invasive phenotype and portend new strategies for developing novel biomarkers and effective treatment modalities for PCa patients.

Downregulation of cytokeratin 18 is associated with paclitaxel-resistance and tumor aggressiveness in prostate cancer

“…As shown in Fig. 2, our data were similar with our previous results (15). Analyses of the high-resolution two-dimensional gels showed that several protein spots were present in DU145 cells, but significantly downregulated in DU145-TxR cells.…”

“…DU145 cells were cultured in Dulbecco's modified Eagle's medium (DMEM; Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS; Gibco, Shanghai, China) at 37˚C in incubator with humidified air and 5% carbon dioxide. The stable paclitaxel-resistant DU145-TxR cells were generated by culturing DU145 cells with stepwise increasing concentrations of paclitaxel (8,15). The initial culture was at 10 nM paclitaxel (Sigma-Aldrich, St. Louis, MO, USA) for 2 days.…”

“…We have previously established a stable paclitaxel-resistant DU145-TxR cell line from the androgen-independent DU145 cell line, which mimics to a certain extent the progression of paclitaxel-resistance in PCa patients (8,15). In the present study, we aimed to identify differentially expressed protein(s) associated with paclitaxel-resistance by comparing the NMP patterns of DU145-TxR cells with that of DU145 cells and further explore the potential mechanisms involved in the drug resistance, which may help develop novel therapeutic strategies as well as clinically useful biomarker(s) for PCa patients.…”

COX-2 dependent regulation of mechanotransduction in human breast cancer cells

“…5). [31][32][33] As expected, PGE 2 caused time-and dose-dependent decreases in the stiffness of isolated human airway smooth muscle cells ( Supplementary Fig. 5) 34 .…”

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

“…Their study also showed reduced CDH1 expression in tumors after neoadjuvant chemotherapy (43). Another study showed that paclitaxel DU-145-resistant cells have greater ZEB1, VIM, and SNAI1 expression (46).…”