Seyfried Thomas N, Chinopoulos Christos
Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
Department of Medical Biochemistry, Semmelweis University, 1094 Budapest, Hungary.
Metabolites. 2021 Aug 25;11(9):572. doi: 10.3390/metabo11090572.
A theory that can best explain the facts of a phenomenon is more likely to advance knowledge than a theory that is less able to explain the facts. Cancer is generally considered a genetic disease based on the somatic mutation theory (SMT) where mutations in proto-oncogenes and tumor suppressor genes cause dysregulated cell growth. Evidence is reviewed showing that the mitochondrial metabolic theory (MMT) can better account for the hallmarks of cancer than can the SMT. Proliferating cancer cells cannot survive or grow without carbons and nitrogen for the synthesis of metabolites and ATP (Adenosine Triphosphate). Glucose carbons are essential for metabolite synthesis through the glycolysis and pentose phosphate pathways while glutamine nitrogen and carbons are essential for the synthesis of nitrogen-containing metabolites and ATP through the glutaminolysis pathway. Glutamine-dependent mitochondrial substrate level phosphorylation becomes essential for ATP synthesis in cancer cells that over-express the glycolytic pyruvate kinase M2 isoform (PKM2), that have deficient OxPhos, and that can grow in either hypoxia (0.1% oxygen) or in cyanide. The simultaneous targeting of glucose and glutamine, while elevating levels of non-fermentable ketone bodies, offers a simple and parsimonious therapeutic strategy for managing most cancers.
一种能最好地解释某一现象事实的理论比一种解释能力较弱的理论更有可能推动知识的进步。基于体细胞突变理论（SMT），癌症通常被认为是一种基因疾病，原癌基因和肿瘤抑制基因的突变会导致细胞生长失调。本文综述的证据表明，线粒体代谢理论（MMT）比SMT能更好地解释癌症的特征。增殖的癌细胞如果没有用于合成代谢物和三磷酸腺苷（ATP）的碳和氮就无法存活或生长。葡萄糖碳通过糖酵解和磷酸戊糖途径对代谢物合成至关重要，而谷氨酰胺氮和碳通过谷氨酰胺分解途径对含氮代谢物和ATP的合成至关重要。谷氨酰胺依赖性线粒体底物水平磷酸化对于过度表达糖酵解型丙酮酸激酶M2亚型（PKM2）、氧化磷酸化功能缺陷且能在低氧（0.1%氧气）或氰化物环境中生长的癌细胞的ATP合成至关重要。同时靶向葡萄糖和谷氨酰胺，同时提高不可发酵酮体的水平，为治疗大多数癌症提供了一种简单而简洁的治疗策略。
