Perez Jesenia M, Ryu Joohyun, Khan Hannah, Shetty Mihir, Parker Emma, D'Arcy Padraig, Zhu Shijia, Bazzaro Martina, Thomas Stefani N
Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2025 Jun 7;26(12):5466. doi: 10.3390/ijms26125466.
ARID1A-deficient ovarian clear cell carcinoma is a highly lethal gynecologic cancer that depends heavily on mitochondrial respiration. Our biochemical and proteomic analyses reveal that ARID1A knockout cells exhibit marked upregulation of specific subunits within mitochondrial electron transport chain (ETC) Complexes I, III, and IV. However, this upregulation does not directly translate into increased sensitivity to broad-spectrum inhibitors targeting these complexes. These findings suggest that broad-spectrum mitochondrial inhibitors may not be effective therapeutic options for ARID1A-deficient cancers. Instead, the selective inhibition of specific ETC subunits may offer a more promising approach to exploit the metabolic vulnerabilities of ARID1A-deficient cells.
缺乏ARID1A的卵巢透明细胞癌是一种高度致命的妇科癌症，严重依赖线粒体呼吸作用。我们的生化和蛋白质组学分析表明，敲除ARID1A的细胞中线粒体电子传递链（ETC）复合体I、III和IV中的特定亚基显著上调。然而，这种上调并没有直接转化为对靶向这些复合体的广谱抑制剂的敏感性增加。这些发现表明，广谱线粒体抑制剂可能不是治疗缺乏ARID1A的癌症的有效选择。相反，选择性抑制特定的ETC亚基可能为利用缺乏ARID1A的细胞的代谢弱点提供一种更有前景的方法。
