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: John J Kim, Bo Yin, Christhunesa S Christudass, Naoki Terada, Krithika Rajagopalan, Ben Fabry, Danielle Y Lee, Takumi Shiraishi, Robert H Getzenberg, Robert W Veltri, Steven S An, Steven M Mooney
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 114 Issue 6 Pg. 1286-93 (Jun 2013) ISSN: 1097-4644 [Electronic] United States
• PMID: 23192682 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• KRT18 protein, human
• KRT8 protein, human
• Keratin-18
• Keratin-19
• Keratin-8
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Cell Line, Tumor (drug effects)
• Cell Movement
• Cell Nucleus (drug effects)
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition
• Humans
• Inhibitory Concentration 50
• Keratin-18 (metabolism)
• Keratin-19 (metabolism)
• Keratin-8 (metabolism)
• Male
• Mice
• Neoplasm Invasiveness
• Paclitaxel (pharmacology)
• Prostatic Neoplasms (drug therapy, pathology)
• Xenograft Model Antitumor Assays