Therapeutic potential of TRPM8 antagonists in prostate cancer

Abstract Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, although its mechanism of action remains unclear. Here, we have characterized and investigated the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular mecha...

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Autores principales:	Marzia Di Donato, Carmine Ostacolo, Pia Giovannelli, Veronica Di Sarno, Isabel M. Gomez Monterrey, Pietro Campiglia, Antimo Migliaccio, Alessia Bertamino, Gabriella Castoria
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fa3e2cc22ff64f05950e4e504372fb1e
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spelling	oai:doaj.org-article:fa3e2cc22ff64f05950e4e504372fb1e2021-12-05T12:11:39ZTherapeutic potential of TRPM8 antagonists in prostate cancer10.1038/s41598-021-02675-42045-2322https://doaj.org/article/fa3e2cc22ff64f05950e4e504372fb1e2021-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02675-4https://doaj.org/toc/2045-2322Abstract Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, although its mechanism of action remains unclear. Here, we have characterized and investigated the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular mechanism underlying their biological activity. Patch-clamp and calcium fluorometric assays were used to characterize the synthesized compounds. Androgen-stimulated prostate cancer-derived cells were challenged with the compounds and the DNA synthesis was investigated in a preliminary screening. The most effective compounds were then employed to inhibit the pro-metastatic behavior of in various PC-derived cells, at different degree of malignancy. The effect of the compounds was then assayed in prostate cancer cell-derived 3D model and the molecular targets of selected compounds were lastly identified using transcriptional and non-transcriptional reporter assays. TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration and invasiveness. They are highly effective in reverting the androgen-induced increase in prostate cancer cell spheroid size. The compounds also revert the proliferation of castrate-resistant prostate cancer cells, provided they express the androgen receptor. In contrast, no effects were recorded in prostate cancer cells devoid of the receptor. Selected antagonists interfere in non-genomic androgen action and abolish the androgen-induced androgen receptor/TRPM8 complex assembly as well as the increase in intracellular calcium levels in prostate cancer cells. Our results shed light in the processes controlling prostate cancer progression and make the transient receptor potential melastatin-8 as a ‘druggable’ target in the androgen receptor-expressing prostate cancers.Marzia Di DonatoCarmine OstacoloPia GiovannelliVeronica Di SarnoIsabel M. Gomez MonterreyPietro CampigliaAntimo MigliaccioAlessia BertaminoGabriella CastoriaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marzia Di Donato Carmine Ostacolo Pia Giovannelli Veronica Di Sarno Isabel M. Gomez Monterrey Pietro Campiglia Antimo Migliaccio Alessia Bertamino Gabriella Castoria Therapeutic potential of TRPM8 antagonists in prostate cancer
description	Abstract Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, although its mechanism of action remains unclear. Here, we have characterized and investigated the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular mechanism underlying their biological activity. Patch-clamp and calcium fluorometric assays were used to characterize the synthesized compounds. Androgen-stimulated prostate cancer-derived cells were challenged with the compounds and the DNA synthesis was investigated in a preliminary screening. The most effective compounds were then employed to inhibit the pro-metastatic behavior of in various PC-derived cells, at different degree of malignancy. The effect of the compounds was then assayed in prostate cancer cell-derived 3D model and the molecular targets of selected compounds were lastly identified using transcriptional and non-transcriptional reporter assays. TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration and invasiveness. They are highly effective in reverting the androgen-induced increase in prostate cancer cell spheroid size. The compounds also revert the proliferation of castrate-resistant prostate cancer cells, provided they express the androgen receptor. In contrast, no effects were recorded in prostate cancer cells devoid of the receptor. Selected antagonists interfere in non-genomic androgen action and abolish the androgen-induced androgen receptor/TRPM8 complex assembly as well as the increase in intracellular calcium levels in prostate cancer cells. Our results shed light in the processes controlling prostate cancer progression and make the transient receptor potential melastatin-8 as a ‘druggable’ target in the androgen receptor-expressing prostate cancers.
format	article
author	Marzia Di Donato Carmine Ostacolo Pia Giovannelli Veronica Di Sarno Isabel M. Gomez Monterrey Pietro Campiglia Antimo Migliaccio Alessia Bertamino Gabriella Castoria
author_facet	Marzia Di Donato Carmine Ostacolo Pia Giovannelli Veronica Di Sarno Isabel M. Gomez Monterrey Pietro Campiglia Antimo Migliaccio Alessia Bertamino Gabriella Castoria
author_sort	Marzia Di Donato
title	Therapeutic potential of TRPM8 antagonists in prostate cancer
title_short	Therapeutic potential of TRPM8 antagonists in prostate cancer
title_full	Therapeutic potential of TRPM8 antagonists in prostate cancer
title_fullStr	Therapeutic potential of TRPM8 antagonists in prostate cancer
title_full_unstemmed	Therapeutic potential of TRPM8 antagonists in prostate cancer
title_sort	therapeutic potential of trpm8 antagonists in prostate cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/fa3e2cc22ff64f05950e4e504372fb1e
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Therapeutic potential of TRPM8 antagonists in prostate cancer

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