title: 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.
authors.affiliation: Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Bo
authors.initials: B
authors.lastname: Yin
authors.forename: Christhunesa S
authors.initials: CS
authors.lastname: Christudass
authors.forename: Naoki
authors.initials: N
authors.lastname: Terada
authors.forename: Krithika
authors.initials: K
authors.lastname: Rajagopalan
authors.forename: Ben
authors.initials: B
authors.lastname: Fabry
authors.forename: Danielle Y
authors.initials: DY
authors.lastname: Lee
authors.forename: Takumi
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Getzenberg
authors.forename: Robert W
authors.initials: RW
authors.lastname: Veltri
authors.forename: Steven S
authors.initials: SS
authors.lastname: An
authors.forename: Steven M
authors.initials: SM
authors.lastname: Mooney
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement; D002467:Cell Nucleus / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D020128:Inhibitory Concentration 50; D053538:Keratin-18 / Q000378:metabolism; D053539:Keratin-19 / Q000378:metabolism; D053533:Keratin-8 / Q000378:metabolism; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C488421:KRT18 protein, human; C426203:KRT8 protein, human; D053538:Keratin-18; D053539:Keratin-19; D053533:Keratin-8; D017239:Paclitaxel