Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden.
Cell Death Differ. 2022 Jul;29(7):1304-1317. doi: 10.1038/s41418-022-01022-y. Epub 2022 Jul 13.
During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.
几十年来，癌症代谢的研究领域一直基于近一个世纪前描述的沃伯格效应。最近，线粒体在癌症发展中的关键作用已经得到证实。由于癌基因和抑癌基因突变以及代谢酶的改变，许多线粒体途径，包括氧化磷酸化、脂肪酸、谷氨酰胺和一碳代谢，在肿瘤中都发生了改变。这导致了代谢重编程，维持了快速的细胞增殖，并可能导致癌细胞用于维持促肿瘤信号通路的活性氧增加，同时避免细胞死亡。现在，人们已经将从线粒体癌症代谢中获得的知识转化为临床实践。对肿瘤进行详细的基因组、转录组和代谢组分析是开发更精确治疗方法的必要条件。靶向代谢线粒体酶的药物的成功应用突出了其在精准医学中的应用潜力，许多治疗候选药物正在临床试验中。然而，开发有效的个性化药物被证明具有挑战性，因此可能需要与其他策略（如细胞毒性药物、免疫疗法和生酮或热量限制饮食）相结合，以发挥其潜力。在这篇综述中，我们总结了不同癌症类型中线粒体的主要特征、代谢途径及其改变。我们还概述了目前的抑制剂，强调了有吸引力的酶靶点，并讨论了将这些方法转化为临床实践的挑战。线粒体在癌症中的作用是不可争议的，为定制化和个性化癌症治疗提供了几个有吸引力的靶点。
