Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy, Harbin, 150001, China.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Nat Commun. 2020 Jun 1;11(1):2689. doi: 10.1038/s41467-020-15396-5.
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.
雄激素拮抗剂恩扎鲁胺（Enz）已改善了去势抵抗性前列腺癌（CRPC）患者的生存。然而，大多数患者最终会产生恩扎鲁胺耐药性，这可能涉及诱导雄激素受体（AR）剪接变体 7（ARv7）。在这里，我们报告在恩扎鲁胺治疗后，高表达单胺氧化酶-A（MAO-A）与 CRPC 患者的 ARv7 检测阳性相关。用苯乙肼或氯丙嗪靶向 MAO-A，这两种药物均为美国食品和药物管理局批准的抗抑郁药，可使恩扎鲁胺耐药（EnzR）细胞对恩扎鲁胺重新敏感，并进一步抑制体外和体内的 EnzR 细胞生长。我们的研究结果表明，恩扎鲁胺增加的 ARv7 表达可以通过改变缺氧 HIF-1α 信号转导来转录增强 MAO-A 表达，从而导致恩扎鲁胺耐药。总之，我们的研究结果表明，用抗抑郁药苯乙肼或氯丙嗪靶向恩扎鲁胺/ARv7/MAO-A 信号可以恢复恩扎鲁胺敏感性，以抑制 EnzR 细胞生长，这可能表明这些抗抑郁药可以克服恩扎鲁胺耐药性，以进一步抑制恩扎鲁胺治疗的 CRPC。
