P38 Mediates Tumor Suppression through Reduced Autophagy and Actin Cytoskeleton Changes in NRAS-Mutant Melanoma

• Published in: Cancers Vol. 15; no. 3; p. 877
• Main Authors: Banik, Ishani, Ghosh, Adhideb, Beebe, Erin, Burja, Blaž, Frank Bertoncelj, Mojca, Dooley, Christopher M, Markkanen, Enni, Dummer, Reinhard, Busch-Nentwich, Elisabeth M, Levesque, Mitchell P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2023; MDPI
• Subjects: Actin; Anisomycin; Apoptosis; Autophagy; Cancer; Cancer therapies; Care and treatment; Cell adhesion & migration; Chloroquine; Collagen; Cytoskeleton; Drug approval; Drug delivery; Drug development; Extracellular matrix; Hydroxychloroquine; Invasiveness; Investigations; Kinases; Localization; MAP kinase; MEK inhibitors; Melanoma; Motility; Mutants; Mutation; Mutation hot spots; Phosphorylation; Physiology; Polymerization; Protein biosynthesis; Proteins; Rapamycin; TOR protein; Transcription factors; Tumor suppressor genes; Tumorigenesis; Tumors; California; mTOR; p38 tumor suppressor; NRAS mutation; melanoma; anisomycin; autophagy
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15030877

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-high 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.