Kim Yonghyo, Doma Viktória, Çakır Uğur, Kuras Magdalena, Betancourt Lazaro Hiram, Pla Indira, Sanchez Aniel, Sugihara Yutaka, Appelqvist Roger, Oskolas Henriett, Lee Boram, Guedes Jéssica, Monnerat Gustavo, Carneiro Gabriel Reis Alves, Nogueira Fábio C S, Domont Gilberto B, Malm Johan, Baldetorp Bo, Wieslander Elisabet, Németh István Balázs, Szász A Marcell, Hong Runyu, Pawłowski Krzysztof, Rezeli Melinda, Kwon Ho Jeong, Timar Jozsef, Fenyö David, Kárpáti Sarolta, Marko-Varga György, Gil Jeovanis
Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Therapeutics and Biotechnology Division, Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Korea.
Cancer. 2025 Jul 1;131(13):e35897. doi: 10.1002/cncr.35897.
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.
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.
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.
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.
黑色素瘤是皮肤癌中最致命的一种，对传统疗法具有抗性，尤其是在晚期和转移阶段。包括氧化磷酸化和线粒体翻译在内的线粒体途径已成为黑色素瘤进展和治疗抗性的关键驱动因素。本研究调查黑色素瘤中的线粒体蛋白质组，以发现新的治疗弱点。
对来自前瞻性队列和尸检组织的151个黑色素瘤相关样本进行定量蛋白质组学分析。差异表达分析确定了与疾病侵袭和治疗抗性相关的线粒体蛋白质。进行功能富集分析并使用线粒体抑制剂进行体外验证，以评估治疗潜力。
线粒体翻译和氧化磷酸化（OXPHOS）在侵袭性黑色素瘤中显著上调，尤其是在BRAF突变型和转移性肿瘤中。使用抗生素（强力霉素、替加环素和阿奇霉素）和OXPHOS抑制剂（VLX600、IACS-010759和BAY 87-2243）抑制线粒体途径在黑色素瘤细胞系中显示出剂量依赖性抗增殖作用，对非癌性黑素细胞无影响。这些治疗破坏了线粒体功能，抑制了关键代谢途径，并诱导了细胞凋亡，突出了靶向这些途径的临床相关性。
本研究揭示线粒体途径是黑色素瘤进展和抗性的关键驱动因素，为在晚期黑色素瘤中靶向线粒体翻译和OXPHOS提供了理论依据。将线粒体抑制剂与现有疗法联合使用可克服治疗抗性并改善患者预后。
