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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.

Authors
  • Go, Simei1, 2
  • Kramer, Thorquil T1, 2
  • Verhoeven, Arthur J1, 2
  • Oude Elferink, Ronald P J1, 2
  • Chang, Jung-Chin3, 4
  • 1 Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. , (Netherlands)
  • 2 Amsterdam Gastroenterology and Metabolism (AG&M) Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. , (Netherlands)
  • 3 Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. [email protected] , (Netherlands)
  • 4 Amsterdam Gastroenterology and Metabolism (AG&M) Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. [email protected] , (Netherlands)
Type
Published Article
Journal
APOPTOSIS
Publisher
Springer-Verlag
Publication Date
Nov 23, 2020
Identifiers
DOI: 10.1007/s10495-020-01648-8
PMID: 33230593
Source
Medline
Keywords
Language
English
License
Unknown

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 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.

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