Proteogenomic Characterization Reveals Therapeutic Opportunities Related to Mitochondrial Function in Melanoma
Author:
Gil JeovanisORCID, Kim Yonghyo, Doma Viktória, Çakır Uğur, Kuras Magdalena, Betancourt Lazaro Hiram, Parada Indira Pla, Sanchez Aniel, Sugihara Yutaka, Appelqvist Roger, Oskolas Henriett, Lee Boram, de Siqueira Guedes Jéssica, Monnerat Gustavo, Alves Carneiro Gabriel Reis, Nogueira Fábio CS, Domont Gilberto B., Malm Johan, Baldetorp Bo, Wieslander Elisabet, Balázs Németh István, Szász A. Marcell, Kwon Ho Jeong, Hong Runyu, Pawłowski Krzysztof, Rezeli Melinda, Tímár József, Fenyö David, Kárpáti Sarolta, Marko-Varga György
Abstract
SummaryThe dynamics of more than 1900 mitochondrial proteins was explored through quantitative proteomics in 151 melanoma-related tissue samples of both surgical and autopsy origin. Dysregulation of mitochondrial pathways in primary tumors, metastases, and peritumoral tissues was correlated with age and survival of patients, as well as with tumor cell proliferation and the BRAF mutation status of the tumors. The outlined proteomic landscape confirmed the central role of a pathologically upregulated mitochondrial translation machinery and oxidative phosphorylation (OXPHOS) in the development, proliferation, and progression of melanomas. Our results from different melanoma cell lines confirmed our findings and we could document that treatments with selected OXPHOS inhibitors and antibiotics successfully impaired tumor cell proliferation. In addition, we provided proteomic evidence on the mechanism-of-action of the different treatments. These observations could contribute to the development of therapeutic approaches targeting the mitochondrial pathology in melanoma.TOC figureHighlightsMitochondrial proteome landscape outlined in 151 melanoma-related samplesMitochondrial Translation and OXPHOS impact disease severity and survivalBRAF V600E mutation correlates with upregulation of mitochondrial energy productionTargeting the mitochondrial OXPHOS and ribosomes impairs tumor cell proliferationTherapeutic opportunities complementary to the standard of care are proposedIn briefMitochondrial proteome profiling of melanomas reveals dysregulation in major metabolic pathways, suggesting a central role of the mitochondria within the development and progression of melanoma. Targeting mitochondrial pathways has the potential to impact the course of the disease, which provides opportunities for complementary drug interventions.
Publisher
Cold Spring Harbor Laboratory
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