Potentiation of ryanodine receptor–mediated calcium release by MAPK is responsible for epidermal transformation and carcinogenesis
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Le résumé fourni par la source
Epidermal growth factor (EGF) induces anchorage-independent growth in promotion-sensitive (P + ) mouse epidermal cell model JB6 primarily through activation of the MAPK/ERK signaling pathway. The β-blocker carvedilol inhibits EGF-promoted JB6 transformation, but the underlying mechanism is unknown. Since carvedilol suppresses overactivated ryanodine receptors (RyRs) independently of its adrenergic blocking effects, we hypothesized that EGF-promoted transformation requires RyR-mediated calcium (Ca 2+ ) release and that carvedilol inhibits transformation via targeting RyRs. All RyR subtypes were present in epidermis and strongly upregulated by ultraviolet (UV) radiation, as demonstrated in an RyR2-tdTomato reporter mouse model. In vitro, EGF induced ERK phosphorylation and RyR2 upregulation and increased RyR agonist 4-chloro-m-cresol (4-CMC)-evoked Ca 2+ release, which is inhibitable by structurally divergent RyR stabilizers and inhibitors of MAPK and PLC, but not by most β-blockers. Expression of constitutively active K-RAS and MEK-1 or UV also potentiated 4-CMC-evoked Ca 2+ release. RyR agonists and the Ca 2+ ionophore ionomycin promoted JB6 transformation while RyR stabilizers, the intracellular Ca 2+ chelator BAPTA/AM, and inhibitors of MAPK and PLC blocked transformation. The RyR shRNAs abolished the transformation-inhibitory effect of carvedilol. The IC 50 values of five carvedilol derivatives for suppressing RyR-mediated Ca 2+ release positively correlated with the IC 50 values for transformation inhibition. In vivo, UV-induced DNA damage and skin inflammation were enhanced by topical 4-CMC treatment but attenuated in the RyR2-E4872Q knock-in mice in which RyR2 activity is reduced. Human skin tissue microarray analysis confirmed spatial colocalization of phospho-ERK and RyR2 in the same tumor areas. Thus, potentiation of RyR-mediated Ca 2+ release by MAPK is an important pathway leading to carcinogenesis.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Potentiation of ryanodine receptor–mediated calcium release by MAPK is responsible for epidermal transformation and carcinogenesis
- Date Crossref
- 10/12/2025
- Éditeur
- National Academy of Sciences
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Capital Medical University Department of Stomatology pays non établi dans la noticeUniversité ou école supérieure
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Beijing Chaoyang Emergency Medical Center pays non établi dans la noticeÉtablissement de santé
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Western University of Health Sciences pays non établi dans la noticeUniversité ou école supérieure
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Chapman University Department of Biomedical and Pharmaceutical Sciences pays non établi dans la noticeUniversité ou école supérieure
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Marshall B. Ketchum University Department of Pharmaceutical Sciences pays non établi dans la noticeUniversité ou école supérieure
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Libin Cardiovascular Institute of Alberta pays non établi dans la noticeStructure de recherche
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University of Calgary Department of Chemistry pays non établi dans la noticeUniversité ou école supérieure
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College of Pharmacy Department of Biotechnology and Pharmaceutical Sciences pays non établi dans la noticeUniversité ou école supérieure
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Cumming School of Medicine Libin Cardiovascular Institute pays non établi dans la noticeUniversité ou école supérieure
Department of Stomatology — Capital Medical University, Beijing Chaoyang Emergency Medical Center et Western University of Health Sciences, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.