Yang Qin, Wang Ling, Liu Jiaye, Cao Wanlu, Pan Qiuwei, Li Meng
Department of general surgery, The Third People's Hospital of Chengdu & the Affiliated Hospital of Southwest Jiaotong University & the second medical school of Chengdu affiliated to Chongqing medical university, Chengdu, Sichuan, 610031, China.
Erasmus MC Cancer Institute, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
Cell Death Discov. 2021 Oct 14;7(1):293. doi: 10.1038/s41420-021-00675-x.
Liver cancer is one of the most common and lethal types of oncological disease in the world, with limited treatment options. New treatment modalities are desperately needed, but their development is hampered by a lack of insight into the underlying molecular mechanisms of disease. It is clear that metabolic reprogramming in mitochondrial function is intimately linked to the liver cancer process, prompting the possibility to explore mitochondrial biochemistry as a potential therapeutic target. Here we report that depletion of mitochondrial DNA, pharmacologic inhibition of mitochondrial electron transport chain (mETC) complex I/complex III, or genetic of mETC complex I restricts cancer cell growth and clonogenicity in various preclinical models of liver cancer, including cell lines, mouse liver organoids, and murine xenografts. The restriction is linked to the production of reactive oxygen species, apoptosis induction and reduced ATP generation. As a result, our findings suggest that the mETC compartment of mitochondria could be a potential therapeutic target in liver cancer.
肝癌是世界上最常见且致命的肿瘤疾病类型之一，治疗选择有限。迫切需要新的治疗方式，但其发展因对疾病潜在分子机制缺乏深入了解而受阻。很明显，线粒体功能的代谢重编程与肝癌进程密切相关，这促使人们有可能探索线粒体生物化学作为潜在治疗靶点。在此我们报告，在包括细胞系、小鼠肝脏类器官和小鼠异种移植瘤等多种肝癌临床前模型中，线粒体DNA的缺失、线粒体电子传递链（mETC）复合体I/复合体III的药理学抑制或mETC复合体I的基因操作均会限制癌细胞的生长和克隆形成能力。这种限制与活性氧的产生、凋亡诱导及ATP生成减少有关。因此，我们的研究结果表明线粒体的mETC区室可能是肝癌的一个潜在治疗靶点。
