TY - JOUR
T1 - The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer
AU - Wang, Keliang
AU - Luo, Jie
AU - Yeh, Shuyuan
AU - You, Bosen
AU - Meng, Jialin
AU - Chang, Philip
AU - Niu, Yuanjie
AU - Li, Gonghui
AU - Lu, Changxue
AU - Zhu, Yezi
AU - Antonarakis, Emmanuel S.
AU - Luo, Jun
AU - Huang, Chi Ping
AU - Xu, Wanhai
AU - Chang, Chawnshang
N1 - 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).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15396-5
DO - 10.1038/s41467-020-15396-5
M3 - Article
C2 - 32483206
AN - SCOPUS:85085854432
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2689
ER -
