{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T11:08:57Z","timestamp":1782731337244,"version":"3.54.5"},"reference-count":69,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T00:00:00Z","timestamp":1675123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect to NRAS-mutant melanoma. We observed that because of p38 activation through treatment with the protein synthesis inhibitor, anisomycin leads to a transient upregulation of several targets of the cAMP pathway, representing a stressed cancer cell state that is often observed by therapeutic doses of MAPK inhibitors in melanoma patients. Meanwhile, genetically induced p38 or its stable transduction leads to a distinct cellular transcriptional state. Contrary to previous work showing an association of invasiveness with high p38 levels in BRAF-mutated melanoma, there was no correlation of p38 expression with NRAS-mutant melanoma invasion, highlighting the difference in BRAF and NRAS-driven melanomas. Although the role of p38 has been reported to be that of both tumor suppressor and oncogene, we show here that p38 specifically plays the role of a tumor suppressor in NRAS-mutant melanoma. Both the transient and stable activation of p38 elicits phosphorylation of mTOR, reported to be a master switch in regulating autophagy. Indeed, we observed a correlation between elevated levels of phosphorylated mTOR and a reduction in LC3 conversion (LCII\/LCI), indicative of suppressed autophagy. Furthermore, a reduction in actin intensity in p38\u2013high cells strongly suggests a role of mTOR in regulating actin and a remodeling in the NRAS-mutant melanoma cells. Therefore, p38 plays a tumor suppressive role in NRAS-mutant melanomas at least partially through the mechanism of mTOR upregulation, suppressed autophagy, and reduced actin polymerization. One or more combinations of MEK inhibitors with either anisomycin, rapamycin, chloroquine\/bafilomycin, and cytochalasin modulate p38 activation, mTOR phosphorylation, autophagy, and actin polymerization, respectively, and they may provide an alternate route to targeting NRAS-mutant melanoma.<\/jats:p>","DOI":"10.3390\/cancers15030877","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T05:33:53Z","timestamp":1675229633000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["P38 Mediates Tumor Suppression through Reduced Autophagy and Actin Cytoskeleton Changes in NRAS-Mutant Melanoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Ishani","family":"Banik","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of Zurich Hospital, University of Zurich, 8091 Zurich, Switzerland"},{"name":"Department of Dermatology, University of San Francisco California, San Francisco, CA 94117, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5160-4571","authenticated-orcid":false,"given":"Adhideb","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Functional Genomics Center Zurich, ETH\/University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3947-3900","authenticated-orcid":false,"given":"Erin","family":"Beebe","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bla\u017e","family":"Burja","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojca","family":"Frank Bertoncelj","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"},{"name":"Team Integrative Biology of Immune-Mediated Inflammatory Diseases, BioMed X Institute, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Dooley","sequence":"additional","affiliation":[{"name":"Max Plank Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7780-8233","authenticated-orcid":false,"given":"Enni","family":"Markkanen","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2279-6906","authenticated-orcid":false,"given":"Reinhard","family":"Dummer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Zurich Hospital, University of Zurich, 8091 Zurich, Switzerland"},{"name":"Department of Dermatology, University of San Francisco California, San Francisco, CA 94117, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Busch-Nentwich","sequence":"additional","affiliation":[{"name":"School of Biological and Behavioural Sciences, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5902-9420","authenticated-orcid":false,"given":"Mitchell","family":"Levesque","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Zurich Hospital, University of Zurich, 8091 Zurich, Switzerland"},{"name":"Department of Dermatology, University of San Francisco California, San Francisco, CA 94117, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,31]]},"reference":[{"key":"ref_1","first-page":"591","article-title":"Vital signs: Melanoma incidence and mortality trends and projections\u2014United States, 1982\u20132030","volume":"64","author":"Guy","year":"2015","journal-title":"MMWR Morb. 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