RIPK4 knockout enhances the antitumor effects of melatonin pretreatment in melanoma cells in vitro and in a xenograft model in zebrafish.
| Title: | RIPK4 knockout enhances the antitumor effects of melatonin pretreatment in melanoma cells in vitro and in a xenograft model in zebrafish. |
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| Authors: | Gazda A; Department of Biophysics and Cancer Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa Street 7, 30-387, Krakow, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Łojasiewicza Street 11, 30-348, Krakow, Poland.; De Paolo R; Consiglio Nazionale delle Ricerche - Istituto di Fisiologia Clinica, Istituto per lo Studio la prevenzione e la Rete Oncologica - Core Research Laboratory, via G. Moruzzi 1, 56124, Pisa, Italy.; Poliseno L; Consiglio Nazionale delle Ricerche - Istituto di Fisiologia Clinica, Istituto per lo Studio la prevenzione e la Rete Oncologica - Core Research Laboratory, via G. Moruzzi 1, 56124, Pisa, Italy.; Prajsnar TK; Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Gronostajowa Street 9, 30-387, Krakow, Poland.; Kleszczyński K; Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 49149, Münster, Germany.; Wolnicka-Glubisz A; Department of Biophysics and Cancer Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa Street 7, 30-387, Krakow, Poland. Electronic address: a.wolnicka-glubisz@uj.edu.pl. |
| Source: | Molecular and cellular endocrinology [Mol Cell Endocrinol] 2026 Aug; Vol. 618, pp. 112810. Date of Electronic Publication: 2026 Apr 28. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: North Holland Publishing Country of Publication: Ireland NLM ID: 7500844 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-8057 (Electronic) Linking ISSN: 03037207 NLM ISO Abbreviation: Mol Cell Endocrinol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Limerick : North Holland Publishing; Original Publication: Amsterdam, North-Holland. |
| MeSH Terms: | Melatonin*/pharmacology ; Melatonin*/therapeutic use ; Melanoma*/pathology ; Melanoma*/drug therapy ; Melanoma*/genetics ; Melanoma*/metabolism ; Antineoplastic Agents*/pharmacology ; Gene Knockout Techniques*; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Receptor, Melatonin, MT1/metabolism ; Receptor, Melatonin, MT2/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Animals ; Zebrafish ; Humans ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Protein Serine-Threonine Kinases |
| Abstract: | Melanoma is an aggressive skin cancer characterized by high metastatic potential and resistance to conventional therapies. Melatonin, a neurohormone known for its circadian and antioxidant functions, has demonstrated anti-proliferative and pro-apoptotic effects in melanoma through both receptor-dependent and receptor-independent mechanisms. Receptor-interacting protein kinase 4 (RIPK4), a regulator of keratinocyte differentiation and the NF-κB and Wnt/β-catenin signaling pathways, has recently emerged as a contributor to melanoma progression and therapy resistance. In this study, we investigated the interaction between melatonin signaling and RIPK4 expression in human melanoma models. We demonstrate that pharmacological concentrations of melatonin significantly reduce cell viability and proliferation in vitro, with a more pronounced effect in RIPK4-knockout (RIPK4.KO) cells. Interestingly, loss of RIPK4 led to the upregulation of melatonin receptors MT1 and MT2, although pharmacological blockade of these receptors failed to reverse melatonin-induced cytotoxicity, suggesting a predominantly receptor-independent mechanism of action. In the zebrafish xenograft model, melanoma cells pretreated with melatonin prior to injection exhibited reduced tumor growth, and the combination with RIPK4 knockout produced an additive anti-tumor effect. Our findings support a novel functional link between RIPK4 and melatonin sensitivity and highlight the potential of combining RIPK4-targeted strategies with melatonin in melanoma therapy.; (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Ki-67; Melanoma; Melatonin; RIPK4; Xenograft model; Zebrafish |
| Substance Nomenclature: | JL5DK93RCL (Melatonin); 0 (Antineoplastic Agents); EC 2.7.1.- (RIPK4 protein, human); 0 (Receptor, Melatonin, MT1); 0 (Receptor, Melatonin, MT2); EC 2.7.11.1 (Protein Serine-Threonine Kinases) |
| Entry Date(s): | Date Created: 20260430 Date Completed: 20260510 Latest Revision: 20260510 |
| Update Code: | 20260511 |
| DOI: | 10.1016/j.mce.2026.112810 |
| PMID: | 42061551 |
| Database: | MEDLINE |
Journal Article