The extracellular lactate-to-pyruvate ratio modulates the sensitivity to oxidative stress-induced apoptosis via the cyto
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The extracellular lactate‑to‑pyruvate ratio modulates the sensitivity to oxidative stress‑induced apoptosis via the cytosolic NADH/NAD+ redox state Simei Go1,2 · Thorquil T. Kramer1,2 · Arthur J. Verhoeven1,2 · Ronald P. J. Oude Elferink1,2 · Jung‑Chin Chang1,2 Accepted: 16 November 2020 © The Author(s) 2020
Abstract 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 stressinduced 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. Keywords Warburg effect · Lactate · Pyruvate · Cytosolic NADH/NAD+ redox state · Raptinal · JNK
Introduction The enhancement of aerobic glycolysis (Warburg effect), first described by Otto Warburg in 1924 [1], supports tumorigenesis in numerous ways. First believed to be caused by dysfunctional mitochondria, it is now established to be Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10495-020-01648-8) contains supplementary material, which is available to authorized users. * Jung‑Chin Chang [email protected] 1
Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Amsterdam Gastroenterology and Metabolism (AG&M) Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
2
the consequence of oncogene activation or tumor suppressor inactivation [2, 3]. While aerobic glycolysis maintains sufficient glycolytic intermediates for multiple biomolecule synthetic pathways [4], most of the carbon skeleton from glucose is secreted in the form of lactat
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