Considerable metabolic reprogramming has been observed in a conserved manner across multiple cancer types, but their true causes remain elusive. We present an analysis of around 50 such reprogrammed metabolisms (RM) including the Warburg effect, nucleotide de novo synthesis, and sialic acid biosynthesis in cancer. Analyses of the biochemical reactions conducted by these RMs, coupled with gene expression data of their catalyzing enzymes, in 7,011 tissues of 14 cancer types, revealed that all RMs produce more H+ than their original metabolisms. These data strongly support a model that these RMs are induced or selected to neutralize a persistent intracellular alkaline stress due to chronic inflammation and local iron overload. To sustain these RMs for survival, cells must find metabolic exits for the nonproton products of these RMs in a continuous manner, some of which pose major challenges, such as nucleotides and sialic acids, because they are electrically charged. This analysis strongly suggests that continuous cell division and other cancerous behaviors are ways for the affected cells to remove such products in a timely and sustained manner. As supporting evidence, this model can offer simple and natural explanations to a range of long-standing open questions in cancer research including the cause of the Warburg effect. SIGNIFICANCE: Inhibiting acidifying metabolic reprogramming could be a novel strategy for treating cancer.

中文翻译：

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诱导癌症中的代谢重编程以增加质子产生。

在多种癌症类型中，均以保守的方式观察到大量的代谢重编程，但其真正原因仍然难以捉摸。我们目前对大约50种这样的重编程代谢（RM）进行分析，包括Warburg效应，核苷酸从头合成和唾液酸生物合成。在14种癌症类型的7,011个组织中，对这些RM进行的生化反应及其催化酶的基因表达数据的分析表明，所有RM均比其原始代谢产生更多的H +。这些数据有力地支持了一个模型，这些模型可以诱导或选择这些RM来中和由于慢性炎症和局部铁超负荷引起的持续的细胞内碱性应激。为了维持这些RM的生存，细胞必须连续地找到这些RM的非质子产物的代谢出口，其中一些构成了重大挑战，例如核苷酸和唾液酸，因为它们带有电荷。该分析强烈表明，连续的细胞分裂和其他癌变行为是受影响的细胞及时，持续地清除此类产物的方法。作为支持证据，该模型可以为癌症研究中包括Warburg效应的原因在内的一系列长期存在的开放性问题提供简单自然的解释。意义：抑制酸化代谢重编程可能是治疗癌症的新策略。该分析强烈表明，连续的细胞分裂和其他癌变行为是受影响的细胞及时，持续地清除此类产物的方法。作为支持证据，该模型可以为癌症研究中包括Warburg效应的原因在内的一系列长期存在的开放性问题提供简单自然的解释。意义：抑制酸化代谢重编程可能是治疗癌症的新策略。该分析强烈表明，连续的细胞分裂和其他癌变行为是受影响的细胞及时，持续地清除此类产物的方法。作为支持证据，该模型可以为癌症研究中包括Warburg效应的原因在内的一系列长期存在的开放性问题提供简单自然的解释。意义：抑制酸化代谢重编程可能是治疗癌症的新策略。