Therapeutic potential of TRPM8 antagonists in prostate cancer.
Androgens
/ pharmacology
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Drug Screening Assays, Antitumor
/ methods
Humans
Male
Neoplasm Invasiveness
Prostatic Neoplasms
/ drug therapy
Receptors, Androgen
Spheroids, Cellular
TRPM Cation Channels
/ agonists
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
received:
12
05
2021
accepted:
22
11
2021
entrez:
2
12
2021
pubmed:
3
12
2021
medline:
20
1
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34853378
doi: 10.1038/s41598-021-02675-4
pii: 10.1038/s41598-021-02675-4
pmc: PMC8636514
doi:
Substances chimiques
Androgens
0
Antineoplastic Agents
0
Receptors, Androgen
0
TRPM Cation Channels
0
TRPM8 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
23232Informations de copyright
© 2021. The Author(s).
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