Mitochondrial proteome landscape unveils key insights into melanoma severity and treatment strategies
(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)
- author
- organization
-
- Clinical Chemistry, Malmö (research group)
- LUCC: Lund University Cancer Centre
- Division for Biomedical Engineering
- Mass Spectrometry
- Clinical Protein Science and Imaging (research group)
- Biomarkers and epidemiology
- EpiHealth: Epidemiology for Health
- Department of Translational Medicine
- LU Profile Area: Light and Materials
- BioMS (research group)
- Medical oncology
- publishing date
- 2025-07-01
- 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
-
- scopus:105008731411
- pmid:40545870
- 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
- 2025-08-05 07:59:03
@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}}, }