NRASQ61K melanoma tumor formation is reduced by p38-MAPK14 activation in zebrafish models and NRAS-mutated human melanoma cells.

Abstract

Oncogenic BRAF and NRAS mutations drive human melanoma initiation. We used transgenic zebrafish to model NRAS-mutant melanoma, and the rapid tumor onset allowed us to study candidate tumor suppressors. We identified P38α-MAPK14 as a potential tumor suppressor in The Cancer Genome Atlas melanoma cohort of NRAS-mutant melanomas, and overexpression significantly increased the time to tumor onset in transgenic zebrafish with NRAS-driven melanoma. Pharmacological activation of P38α-MAPK14 using anisomycin reduced in vitro viability of melanoma cultures, which we confirmed by stable overexpression of p38α. We observed that the viability of MEK inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK inhibition. Our study demonstrates that activating the p38α-MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo. SIGNIFICANCE: The significance of our study is in the accountability of NRAS mutations in melanoma. We demonstrate here that activation of p38α-MAPK14 pathway can abrogate NRAS-mutant melanoma which is contrary to the previously published role of p38α-MAPK14 pathway in BRAF mutant melanoma. These results implicate that BRAF and NRAS-mutant melanoma may not be identical biologically. We also demonstrate the translational benefit of our study by using a small molecule compound-anisomycin (already in use for other diseases in clinical trials) to activate p38α-MAPK14 pathway.

• Authors: Ishani Banik, Phil F Cheng, Christopher M Dooley, Jana Travnickova, Munise Merteroglu, Reinhard Dummer, Elizabeth E Patton, Elisabeth M Busch-Nentwich, Mitchell P Levesque
• Journal: Pigment cell & melanoma research (Pigment Cell Melanoma Res) Vol. 34 Issue 2 Pg. 150-162 (03 2021) ISSN: 1755-148X [Electronic] England
• PMID: 32910840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Membrane Proteins
• Protein Kinase Inhibitors
• Protein Synthesis Inhibitors
• Anisomycin
• Mitogen-Activated Protein Kinase 14
• GTP Phosphohydrolases
• NRAS protein, human

Topics

• Animals
• Anisomycin (pharmacology)
• Apoptosis
• Cell Proliferation
• GTP Phosphohydrolases (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma (genetics, metabolism, pathology, prevention & control)
• Membrane Proteins (genetics)
• Mitogen-Activated Protein Kinase 14 (antagonists & inhibitors, genetics, metabolism)
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Protein Synthesis Inhibitors (pharmacology)
• Tumor Cells, Cultured
• Zebrafish