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Muscarinic receptors promote castration-resistant growth of prostate cancer through a FAK–YAP signaling axis


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.

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Fig. 1: Frequent overexpression of m1 and m3 in PCa and gene amplification and gain in CRPC.
Fig. 2: m1 and m3 are upregulated in CRPC cell lines, and activation of m1 and m3 induces castration-resistant growth of PCa cells.
Fig. 3: m1 and m3 signaling activate FAK and YAP, resulting in castration-resistant growth.
Fig. 4: Clinical impact of FAK gene expression on PCa.
Fig. 5: Pharmacological inhibition of FAK blocks carbachol-induced YAP activation and proliferation.

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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. YG initiated the study; YG and JSG designed the study and experiments; YG performed the genomic analyses; YG, TA, HI, NA, KA performed in vitro experiments, YG and MG performed immunofluorescence experiments, YG, NA and JSG prepared the manuscript, XF, ZW, NA and JSG provided advice and supervised the project. All authors discussed the results and reviewed the manuscript.

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Correspondence to J. Silvio Gutkind.

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JSG is member of the Advisory Board of Oncoceutics and Domain Therapeutics.

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Goto, Y., Ando, T., Izumi, H. et al. Muscarinic receptors promote castration-resistant growth of prostate cancer through a FAK–YAP signaling axis. Oncogene 39, 4014–4027 (2020).

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