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Muscarinic receptors promote castration-resistant growth of prostate cancer through a FAK-YAP signaling axis.
- Source :
-
Oncogene [Oncogene] 2020 May; Vol. 39 (20), pp. 4014-4027. Date of Electronic Publication: 2020 Mar 23. - Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Focal Adhesion Kinase 1 genetics
Humans
Male
Neoplasm Proteins genetics
PC-3 Cells
Prostatic Neoplasms, Castration-Resistant genetics
Prostatic Neoplasms, Castration-Resistant pathology
Receptor, Muscarinic M1 genetics
Receptor, Muscarinic M3 genetics
Transcription Factors genetics
YAP-Signaling Proteins
Adaptor Proteins, Signal Transducing metabolism
Focal Adhesion Kinase 1 metabolism
Neoplasm Proteins metabolism
Prostatic Neoplasms, Castration-Resistant metabolism
Receptor, Muscarinic M1 biosynthesis
Receptor, Muscarinic M3 biosynthesis
Signal Transduction
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 39
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 32205868
- Full Text :
- https://doi.org/10.1038/s41388-020-1272-x