Inhibition of CXCR4/CXCL12 signaling axis by ursolic acid leads to suppression of metastasis in transgenic adenocarcinoma of mouse prostate model

Authors

  • Muthu K. Shanmugam,

    1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
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    • M.K.S. and K.A.M. contributed equally to this work.

  • Kanjoormana A. Manu,

    1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
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    • M.K.S. and K.A.M. contributed equally to this work.

  • Tina H. Ong,

    1. Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610
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  • Lalitha Ramachandran,

    1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
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  • Rohit Surana,

    1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
    2. Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456
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  • Pradeep Bist,

    1. Department of Physiology, National University of Singapore, Singapore 117597
    2. Immunology Program, National University of Singapore, Singapore 117597
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  • Lina H.K Lim,

    1. Department of Physiology, National University of Singapore, Singapore 117597
    2. Immunology Program, National University of Singapore, Singapore 117597
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  • Alan Prem Kumar,

    1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
    2. Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456
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  • Kam M. Hui,

    1. Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610
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  • Gautam Sethi

    Corresponding author
    1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
    • Department of Pharmacology, Yong Lo o Lin School of Medicine, National University of Singapore, Singapore 117597
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    • Tel.: 65-65163267, Fax: 65-68737690


Abstract

Increasing evidences indicate that CXCR4/CXCL12 signaling pathway plays a pivotal role in the process of distant site metastasis that accounts for more than 90% of prostate cancer related deaths in patients. Thus, novel drugs that can downregulate CXCR4/CXCL12 axis have a great potential in the treatment of metastatic prostate cancer. In this report, we tested an agent, ursolic acid (UA) for its ability to modulate CXCR4 expression in prostate cancer cell lines and inhibit metastasis in vivo in transgenic adenocarcinoma of mouse prostate (TRAMP) model. We observed that UA downregulated the expression of CXCR4 in prostate cancer cells irrespective of their HER2 status in a dose- and time-dependent manner. Neither proteasome inhibitor nor lysosomal stabilization had any effect on UA-induced decrease in CXCR4 expression. When investigated for the molecular mechanisms, it was observed that the downregulation of CXCR4 was due to transcriptional regulation as indicated by downregulation of mRNA expression, inhibition of NF-κB activation and modulation of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by UA further correlated with the inhibition of CXCL12-induced migration and invasion in prostate cancer cells. Finally, we also found that UA treatment can inhibit metastasis of prostate cancer to distal organs, including lung and liver and suppress CXCR4 expression levels in the prostate tissues of TRAMP mice. Overall, our experimental findings suggest that UA exerts its antimetastatic effects through the suppression of CXCR4 expression in prostate cancer both in vitro and in vivo.

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