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


Type
Article
Change log
Authors
Banik, Ishani 
Cheng, Phil F 
Dooley, Christopher M 
Travnickova, Jana 
Merteroglu, Munise 
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.

Description
Keywords
NRAS mutation, Zebrafish, anisomycin, melanoma, p38-MAPK14 pathway, Animals, Anisomycin, Apoptosis, Cell Proliferation, GTP Phosphohydrolases, Gene Expression Regulation, Neoplastic, Humans, Melanoma, Membrane Proteins, Mitogen-Activated Protein Kinase 14, Mutation, Protein Kinase Inhibitors, Protein Synthesis Inhibitors, Tumor Cells, Cultured, Zebrafish
Journal Title
Pigment Cell and Melanoma Research
Conference Name
Journal ISSN
0893-5785
1755-148X
Volume Title
Publisher
Blackwell Publishing Inc.
Rights
All rights reserved
Sponsorship
This project has received funding from the European Union’s Horizon 2020 432 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 641458. The 433 work carried out at the University of Edinburgh was partly funded by EEP, MRC HGU Programme 434 (MC_UU_00007/9), European Research Council (ZF-MEL-CHEMBIO-648489), and L'Oreal-Melanoma 435 Research Alliance (401181).