The advantages of the Warburg effect on tumor growth and progression are well recognized. However, the relevance of the Warburg effect for the inherent resistance to apoptosis of cancer cells has received much less attention. Here, we show here that the Warburg effect modulates the extracellular lactate-to-pyruvate ratio, which profoundly regulates the sensitivity towards apoptosis induced by oxidative stress in several cell lines. To induce oxidative stress, we used the rapid apoptosis inducer Raptinal. We observed that medium conditioned by HepG2 cells has a high lactate-to-pyruvate ratio and confers resistance to Raptinal-induced apoptosis. In addition, imposing a high extracellular lactate-to-pyruvate ratio in media reduces the cytosolic NADH/NAD⁺ redox state and protects against Raptinal-induced apoptosis. Conversely, a low extracellular lactate-to-pyruvate ratio oxidizes the cytosolic NADH/NAD⁺ redox state and sensitizes HepG2 cells to oxidative stress-induced apoptosis. Mechanistically, a high extracellular lactate-to-pyruvate ratio decreases the activation of JNK and Bax under oxidative stress, thereby inhibiting the intrinsic apoptotic pathway. Our observations demonstrate that the Warburg effect of cancer cells generates an anti-apoptotic extracellular environment by elevating the extracellular lactate-to-pyruvate ratio which desensitizes cancer cells towards apoptotic insults. Consequently, our study suggests that the Warburg effect can be targeted to reverse the lactate-to-pyruvate ratios in the tumor microenvironment and thereby re-sensitize cancer cells to oxidative stress-inducing therapies.

Warburg 效应对肿瘤生长和进展的优势是公认的。然而，Warburg 效应与癌细胞固有的抗凋亡能力的相关性却很少受到关注。在这里，我们在这里展示了 Warburg 效应调节细胞外乳酸与丙酮酸的比率，这在几个细胞系中深刻地调节了对氧化应激诱导的细胞凋亡的敏感性。为了诱导氧化应激，我们使用了快速凋亡诱导剂 Raptinal。我们观察到由 HepG2 细胞调节的培养基具有高乳酸与丙酮酸的比例，并赋予对 Raptinal 诱导的细胞凋亡的抗性。此外，在培养基中提高细胞外乳酸与丙酮酸的比例可降低细胞溶质 NADH/NAD ⁺氧化还原状态并防止 Raptinal 诱导的细胞凋亡。相反，细胞外乳酸与丙酮酸的比例低会氧化细胞溶质 NADH/NAD ⁺氧化还原状态并使 HepG2 细胞对氧化应激诱导的细胞凋亡敏感。从机制上讲，高细胞外乳酸与丙酮酸的比例会降低氧化应激下 JNK 和 Bax 的活化，从而抑制内在的凋亡途径。我们的观察表明，癌细胞的 Warburg 效应通过提高细胞外乳酸与丙酮酸的比率来产生抗凋亡的细胞外环境，从而使癌细胞对凋亡损伤不敏感。因此，我们的研究表明，Warburg 效应可以靶向逆转肿瘤微环境中乳酸与丙酮酸的比例，从而使癌细胞对氧化应激诱导疗法重新敏感。