It has been observed that both cancer tissue cells and normal proliferating cells (NPCs) have the Warburg effect. Our goal here is to demonstrate that they do this for different reasons. To accomplish this, we have analyzed the transcriptomic data of over 7000 cancer and control tissues of 14 cancer types in TCGA and data of five NPC types in GEO. Our analyses reveal that NPCs accumulate large quantities of ATPs produced by the respiration process before starting the Warburg effect, to raise the intracellular pH from ∼6.8 to ∼7.2 and to prepare for cell division energetically. Once cell cycle starts, the cells start to rely on glycolysis for ATP generation followed by ATP hydrolysis and lactic acid release, to maintain the elevated intracellular pH as needed by cell division since together the three processes are pH neutral. The cells go back to the normal respiration-based ATP production once the cell division phase ends. In comparison, cancer cells have reached their intracellular pH at ∼7.4 from top down as multiple acid-loading transporters are up-regulated and most acid-extruding ones except for lactic acid exporters are repressed. Cancer cells use continuous glycolysis for ATP production as way to acidify the intracellular space since the lactic acid secretion is decoupled from glycolysis-based ATP generation and is pH balanced by increased expressions of acid-loading transporters. Co-expression analyses suggest that lactic acid secretion is regulated by external, non-pH related signals. Overall, our data strongly suggest that the two cell types have the Warburg effect for very different reasons.

中文翻译：

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华宝在癌症和正常增殖细胞中的作用：两个同名故事。

已经观察到癌细胞组织细胞和正常增殖细胞（NPC）都具有沃堡效应。我们的目标是证明他们出于不同的原因这样做。为此，我们分析了TCGA中14种癌症类型的7000多种癌症和对照组织的转录组数据，以及GEO中5种NPC类型的数据。我们的分析表明，NPC在开始出现Warburg效应之前会积累大量呼吸过程产生的ATP，从而使细胞内pH从6.8升高到7.2，并为能量分裂做好准备。一旦细胞周期开始，细胞就开始依靠糖酵解来生成ATP，然后再进行ATP水解和释放乳酸，以维持细胞分裂所需的升高的细胞内pH，因为这三个过程共同是pH中性的。一旦细胞分裂阶段结束，细胞就会恢复正常的基于呼吸的ATP产生。相比之下，癌细胞的细胞内pH从上至下达到了约7.4的细胞内pH，这是因为多个载酸转运蛋白被上调，而除乳酸出口蛋白以外的大多数酸挤压转运蛋白被抑制。癌细胞利用连续的糖酵解来产生ATP，以此来酸化细胞内空间，因为乳酸分泌与基于糖酵解的ATP产生脱钩，并且由于酸负荷转运蛋白的表达增加而使pH平衡。共表达分析表明乳酸分泌受外部非pH相关信号调节。总体而言，我们的数据强烈暗示两种细胞类型具有沃堡效应的原因非常不同。