机构:[1]Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA[2]Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan[3]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China[4]Department of Orthodontics, Applied Life Sciences, Hiroshima University Institute of Biomedical & Health Sciences, Hiroshima, Japan
Prostate cancer (PCa) innervation contributes to the progression of PCa. However, the precise impact of innervation on PCa cells is still poorly understood. By focusing on muscarinic receptors, which are activated by the nerve-derived neurotransmitter acetylcholine, we show that muscarinic receptors 1 and 3 (m1 and m3) are highly expressed in PCa clinical specimens compared with all other cancer types, and that amplification or gain of their corresponding encoding genes (CHRM1 and CHRM3, respectively) represent a worse prognostic factor for PCa progression free survival. Moreover, m1 and m3 gene gain or amplification is frequent in castration-resistant PCa (CRPC) compared with hormone-sensitive PCa (HSPC) specimens. This was reflected in HSPC-derived cells, which show aberrantly high expression of m1 and m3 under androgen deprivation mimicking castration and androgen receptor inhibition. We also show that pharmacological activation of m1 and m3 signaling is sufficient to induce the castration-resistant growth of PCa cells. Mechanistically, we found that m1 and m3 stimulation induces YAP activation through FAK, whose encoding gene, PTK2 is frequently amplified in CRPC cases. Pharmacological inhibition of FAK and knockdown of YAP abolished m1 and m3-induced castration-resistant growth of PCa cells. Our findings provide novel therapeutic opportunities for muscarinic-signal-driven CRPC progression by targeting the FAK-YAP signaling axis.
基金:
YG is supported by the JSPS Overseas Research
Fellowships and the Uehara Memorial Foundation Research Fellowship.
XF is supported by 111 Project of MOE (B14038) China, the
National Natural Science Foundation (81402230, 81672677) China.
MG is supported by FIRC-AIRC fellowship for abroad (Italian
Foundation for cancer research). We thank La Jolla Institute Microscopy
Core Facility for professional advice and guidance, in particular
Zbigniew Mikulski. This work was supported by S10OD021831.
语种:
外文
PubmedID:
中科院(CAS)分区:
出版当年[2020]版:
大类|1 区医学
小类|1 区生化与分子生物学1 区肿瘤学1 区遗传学2 区细胞生物学
最新[2023]版:
大类|1 区医学
小类|1 区生化与分子生物学1 区遗传学2 区细胞生物学2 区肿瘤学
第一作者:
第一作者机构:[1]Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
通讯作者:
推荐引用方式(GB/T 7714):
Yusuke Goto,Toshinori Ando,Hiroki Izumi,et al.Muscarinic receptors promote castration-resistant growth of prostate cancer through a FAK-YAP signaling axis.[J].Oncogene.2020,39(20):4014-4027.doi:10.1038/s41388-020-1272-x.
APA:
Yusuke Goto,Toshinori Ando,Hiroki Izumi,Xiaodong Feng,Nadia Arang...&J. Silvio Gutkind.(2020).Muscarinic receptors promote castration-resistant growth of prostate cancer through a FAK-YAP signaling axis..Oncogene,39,(20)
MLA:
Yusuke Goto,et al."Muscarinic receptors promote castration-resistant growth of prostate cancer through a FAK-YAP signaling axis.".Oncogene 39..20(2020):4014-4027