Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies

Kim, Yonghyo LU ; Doma, Viktória ; Çakır, Uğur ; Kuras, Magdalena LU orcid ; Betancourt, Lazaro Hiram LU ; Pla, Indira LU orcid ; Sanchez, Aniel LU ; Sugihara, Yutaka LU ; Appelqvist, Roger LU and Oskolas, Henriett LU , et al. (2025) In Cancer 131(13).
Abstract

BACKGROUND: Melanoma, the deadliest form of skin cancer, exhibits resistance to conventional therapies, particularly in advanced and metastatic stages. Mitochondrial pathways, including oxidative phosphorylation and mitochondrial translation, have emerged as critical drivers of melanoma progression and therapy resistance. This study investigates the mitochondrial proteome in melanoma to uncover novel therapeutic vulnerabilities.

METHODS: Quantitative proteomics was performed on 151 melanoma-related samples from a prospective cohort and postmortem tissues. Differential expression analysis identified mitochondrial proteins linked to disease aggression and treatment resistance. Functional enrichment analyses and in vitro validation... (More)

BACKGROUND: Melanoma, the deadliest form of skin cancer, exhibits resistance to conventional therapies, particularly in advanced and metastatic stages. Mitochondrial pathways, including oxidative phosphorylation and mitochondrial translation, have emerged as critical drivers of melanoma progression and therapy resistance. This study investigates the mitochondrial proteome in melanoma to uncover novel therapeutic vulnerabilities.

METHODS: Quantitative proteomics was performed on 151 melanoma-related samples from a prospective cohort and postmortem tissues. Differential expression analysis identified mitochondrial proteins linked to disease aggression and treatment resistance. Functional enrichment analyses and in vitro validation using mitochondrial inhibitors were conducted to evaluate therapeutic potential.

RESULTS: Mitochondrial translation and oxidative phosphorylation (OXPHOS) were significantly upregulated in aggressive melanomas, particularly in BRAF-mutant and metastatic tumors. Inhibition of mitochondrial pathways using antibiotics (doxycycline, tigecycline, and azithromycin) and OXPHOS inhibitors (VLX600, IACS-010759, and BAY 87-2243) demonstrated dose-dependent antiproliferative effects in melanoma cell lines, sparing noncancerous melanocytes. These treatments disrupted mitochondrial function, suppressed key metabolic pathways, and induced apoptosis, highlighting the clinical relevance of targeting these pathways.

CONCLUSIONS: This study reveals mitochondrial pathways as critical drivers of melanoma progression and resistance, providing a rationale for targeting mitochondrial translation and OXPHOS in advanced melanoma. Combining mitochondrial inhibitors with existing therapies could overcome treatment resistance and improve patient outcomes.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Melanoma/pathology, Proteome/metabolism, Mitochondria/metabolism, Oxidative Phosphorylation/drug effects, Skin Neoplasms/pathology, Cell Line, Tumor, Mitochondrial Proteins/metabolism, Proteomics/methods, Female, Apoptosis/drug effects, Male, Proto-Oncogene Proteins B-raf/genetics, Prospective Studies, Cell Proliferation/drug effects, Drug Resistance, Neoplasm, Middle Aged
in
Cancer
volume
131
issue
13
article number
e35897
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:40545870
  • scopus:105008731411
ISSN
1097-0142
DOI
10.1002/cncr.35897
language
English
LU publication?
yes
additional info
© 2025 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.
id
69abfc43-90c8-4c1c-807d-132eddd7fdc5
date added to LUP
2025-08-04 16:19:46
date last changed
2025-08-19 05:14:10
@article{69abfc43-90c8-4c1c-807d-132eddd7fdc5,
  abstract     = {{<p>BACKGROUND: Melanoma, the deadliest form of skin cancer, exhibits resistance to conventional therapies, particularly in advanced and metastatic stages. Mitochondrial pathways, including oxidative phosphorylation and mitochondrial translation, have emerged as critical drivers of melanoma progression and therapy resistance. This study investigates the mitochondrial proteome in melanoma to uncover novel therapeutic vulnerabilities.</p><p>METHODS: Quantitative proteomics was performed on 151 melanoma-related samples from a prospective cohort and postmortem tissues. Differential expression analysis identified mitochondrial proteins linked to disease aggression and treatment resistance. Functional enrichment analyses and in vitro validation using mitochondrial inhibitors were conducted to evaluate therapeutic potential.</p><p>RESULTS: Mitochondrial translation and oxidative phosphorylation (OXPHOS) were significantly upregulated in aggressive melanomas, particularly in BRAF-mutant and metastatic tumors. Inhibition of mitochondrial pathways using antibiotics (doxycycline, tigecycline, and azithromycin) and OXPHOS inhibitors (VLX600, IACS-010759, and BAY 87-2243) demonstrated dose-dependent antiproliferative effects in melanoma cell lines, sparing noncancerous melanocytes. These treatments disrupted mitochondrial function, suppressed key metabolic pathways, and induced apoptosis, highlighting the clinical relevance of targeting these pathways.</p><p>CONCLUSIONS: This study reveals mitochondrial pathways as critical drivers of melanoma progression and resistance, providing a rationale for targeting mitochondrial translation and OXPHOS in advanced melanoma. Combining mitochondrial inhibitors with existing therapies could overcome treatment resistance and improve patient outcomes.</p>}},
  author       = {{Kim, Yonghyo and Doma, Viktória and Çakır, Uğur and Kuras, Magdalena and Betancourt, Lazaro Hiram and Pla, Indira and Sanchez, Aniel and Sugihara, Yutaka and Appelqvist, Roger and Oskolas, Henriett and Lee, Boram and Guedes, Jéssica and Monnerat, Gustavo and Carneiro, Gabriel Reis Alves and Nogueira, Fábio C S and Domont, Gilberto B and Malm, Johan and Baldetorp, Bo and Wieslander, Elisabet and Németh, István Balázs and Szász, A Marcell and Hong, Runyu and Pawłowski, Krzysztof and Rezeli, Melinda and Kwon, Ho Jeong and Timar, Jozsef and Fenyö, David and Kárpáti, Sarolta and Marko-Varga, György and Gil, Jeovanis}},
  issn         = {{1097-0142}},
  keywords     = {{Humans; Melanoma/pathology; Proteome/metabolism; Mitochondria/metabolism; Oxidative Phosphorylation/drug effects; Skin Neoplasms/pathology; Cell Line, Tumor; Mitochondrial Proteins/metabolism; Proteomics/methods; Female; Apoptosis/drug effects; Male; Proto-Oncogene Proteins B-raf/genetics; Prospective Studies; Cell Proliferation/drug effects; Drug Resistance, Neoplasm; Middle Aged}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{13}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Cancer}},
  title        = {{Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies}},
  url          = {{http://dx.doi.org/10.1002/cncr.35897}},
  doi          = {{10.1002/cncr.35897}},
  volume       = {{131}},
  year         = {{2025}},
}