TRPM8 indicates poor prognosis in colorectal cancer patients and its pharmacological targeting reduces tumour growth in mice by inhibiting Wnt/β-catenin signalling.

Autor: Pagano E; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Romano B; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Cicia D; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Iannotti FA; Institute of Biomolecular Chemistry ICB, CNR, Pozzuoli, Naples, Italy., Venneri T; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Lucariello G; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Nanì MF; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Cattaneo F; Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., De Cicco P; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., D'Armiento M; Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., De Luca M; Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Lionetti R; Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Lama S; Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy., Stiuso P; Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy., Zoppoli P; Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy., Falco G; Istituto di Ricerche Genetiche Gaetano Salvatore Biogem Scarl, Ariano Irpino, Italy.; Department of Biology, University of Naples Federico II, Naples, Italy., Marchianò S; Department of Medicine and Surgery, University of Perugia, Perugia, Italy., Fiorucci S; Department of Medicine and Surgery, University of Perugia, Perugia, Italy., Capasso R; Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy., Di Marzo V; Institute of Biomolecular Chemistry ICB, CNR, Pozzuoli, Naples, Italy.; Institut sur la Nutrition et les Aliments Fonctionnels, Centre NUTRISS, École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, Canada.; Centre de Recherche de l'Institut de Pneumologie et Cardiologie de l'Université Laval, Faculté de Médecine, Université Laval, Québec, Canada.; Canada Research Excellence Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, Canada., Borrelli F; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Izzo AA; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2023 Jan; Vol. 180 (2), pp. 235-251. Date of Electronic Publication: 2022 Oct 17.
DOI: 10.1111/bph.15960
Abstrakt: Background and Purpose: Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC).
Experimental Approach: TRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8 -/- mice in models of sporadic and colitis-associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC.
Key Results: TRPM8 is overexpressed in colon primary tumours and in CD326 + tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt-Frizzled signalling hyperactivation and adenomatous polyposis coli down-regulation. In sporadic and colitis-associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/β-catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of β-catenin and its target oncogenes such as C-Myc and Cyclin D1.
Conclusion and Implications: Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC.
(© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje