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The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer

Author

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  • Keliang Wang

    (The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy
    University of Rochester Medical Center)

  • Jie Luo

    (University of Rochester Medical Center)

  • Shuyuan Yeh

    (University of Rochester Medical Center)

  • Bosen You

    (The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy
    University of Rochester Medical Center)

  • Jialin Meng

    (University of Rochester Medical Center)

  • Philip Chang

    (Kaiser Permanente Santa Clara Medical Center)

  • Yuanjie Niu

    (Tianjin Medical University)

  • Gonghui Li

    (Zhejiang University School of Medicine)

  • Changxue Lu

    (Johns Hopkins University School of Medicine)

  • Yezi Zhu

    (Johns Hopkins University School of Medicine)

  • Emmanuel S. Antonarakis

    (Johns Hopkins University School of Medicine)

  • Jun Luo

    (Johns Hopkins University School of Medicine)

  • Chi-Ping Huang

    (China Medical University and Hospital)

  • Wanhai Xu

    (The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy)

  • Chawnshang Chang

    (University of Rochester Medical Center
    China Medical University and Hospital)

Abstract

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.

Suggested Citation

  • Keliang Wang & Jie Luo & Shuyuan Yeh & Bosen You & Jialin Meng & Philip Chang & Yuanjie Niu & Gonghui Li & Changxue Lu & Yezi Zhu & Emmanuel S. Antonarakis & Jun Luo & Chi-Ping Huang & Wanhai Xu & Cha, 2020. "The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15396-5
    DOI: 10.1038/s41467-020-15396-5
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