1. Targeting mitochondria in melanoma: Interplay between MAPK signaling pathway and mitochondrial dynamics.
- Author
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Ferraz LS, Costa RTD, Costa CAD, Ribeiro CAJ, Arruda DC, Maria-Engler SS, and Rodrigues T
- Subjects
- Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Dynamins antagonists & inhibitors, Dynamins genetics, Dynamins metabolism, Humans, Melanocytes drug effects, Melanocytes metabolism, Melanocytes pathology, Mitochondria drug effects, Mitochondria metabolism, Mitogen-Activated Protein Kinases metabolism, Molecular Targeted Therapy, Mutation, Oxidative Phosphorylation drug effects, Phosphorylation drug effects, Proto-Oncogene Proteins B-raf metabolism, Signal Transduction, Antineoplastic Agents pharmacology, Gene Expression Regulation, Neoplastic, Mitochondrial Dynamics drug effects, Mitogen-Activated Protein Kinases genetics, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics, Vemurafenib pharmacology
- Abstract
Melanoma is a malignant proliferative disease originated in melanocytes, characterized by high metastatic activity and by the activation of oncogenes, such as B-RAF (40-60% of cases). Recent studies have shown that vemurafenib (a MAPK inhibitor) promoted disturbance of mitochondrial bioenergetics, although underlying mechanisms are not fully comprehended. Here we showed that MAPK inhibition by vemurafenib in B-RAF
V600E -mutated human melanoma culminated in the inhibition of DRP1 phosphorylation, associated to a large mitochondrial network remodeling to the hyperfused phenotype, and increased oxidative phosphorylation capacity. Such alterations may be associated to melanoma resistance to vemurafenib, since the impairment of oxidative phosphorylation increased the vemurafenib cytotoxicity. These results point to the potential of mitochondrial dynamics as a targetable pathway in melanoma., 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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