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, Chawnshang Chang

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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.

Original languageEnglish (US)
Article number2689
JournalNature communications
Issue number1
StatePublished - Dec 1 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by George Whipple Professorship and Natural Science Foundations of Heilongjiang Province of China (H2016030). We acknowledged Karen Wolf for checking the text thoroughly for accuracy and grammar.

Publisher Copyright:
© 2020, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't


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