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

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 () and Chawnshang Chang ()
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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
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
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

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15396-5

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