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Journal of Cellular Biochemistry

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

Authors

  • John J. Kim,

    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
    2. Department of Biomedical Engineering, Whiting School of Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
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  • Bo Yin,

    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
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  • Christhunesa S. Christudass,

    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
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  • Naoki Terada,

    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
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  • Krithika Rajagopalan,

    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
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  • Ben Fabry,

    1. Department of Physics, University of Erlangen–Nuremberg, Erlangen, Germany
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  • Danielle Y. Lee,

    1. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
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  • Takumi Shiraishi,

    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
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  • Robert H. Getzenberg,

    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
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  • Robert W. Veltri,

    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
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  • Steven S. An,

    Corresponding author
    1. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205
    2. Physical Sciences in Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21205
    3. In Vivo Cellular and Molecular Imaging Center, The Johns Hopkins University, Baltimore, Maryland 21205
    • Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Room E7616, Baltimore, MD 21205.
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  • Steven M. Mooney

    Corresponding author
    1. Department of Urology, James Buchanan Brady Urological Institute, Baltimore, Maryland 21287
    • Department of Urology and Oncology, James Buchanan Brady Urological Institute, 600 N. Wolfe Street, 129B Marburg, Baltimore, MD 21287.
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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. J. Cell. Biochem. 114: 1286–1293, 2013. © 2012 Wiley Periodicals, Inc.

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