The extracellular lactate-to-pyruvate ratio modulates the sensitivity to oxidative stress-induced apoptosis via the cytosolic NADH/NAD+ redox state

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.

The LncRNA DUXAP10 Could Function as a Promising Oncogene in Human Cancer

“…Cell proliferation and apoptosis are fundamental for normal cell growth and development. Abnormal cell growth is a key marker for cancer (Shi et al, 2020a;Go et al, 2021;. It has been shown that microRNA-1914 could increase the effect of DUXAP10 on cell proliferation and apoptosis through activation of the GPR39-mediated PI3K/AKT/mTOR pathway in HCC Hep3B and MHCC-97L (Sun et al, 2019) cells (Figure 2).…”

Insights on the role of l-lactate as a signaling molecule in skin aging

“…Even this role in autophagy might have a hormetic cause, as the same l -lactate has an inhibitory action on autophagy when cells have lost their stress responsivity, such as in tumors (Matsuo et al 2019 ). Again, in this perspective, l -lactate should exert a fundamental regulatory activity even on apoptosis (Go et al 2021 ). At least on HepG2 cell lines, the increase in the extracellular lactate-to-pyruvate ratio has the ability to reduce the cytosol NADH/NAD + redox state and inhibiting stress-induced apoptosis (Go et al 2021 ).…”

“…Again, in this perspective, l -lactate should exert a fundamental regulatory activity even on apoptosis (Go et al 2021 ). At least on HepG2 cell lines, the increase in the extracellular lactate-to-pyruvate ratio has the ability to reduce the cytosol NADH/NAD + redox state and inhibiting stress-induced apoptosis (Go et al 2021 ). Moreover, high extracellular l -lactate inhibits the intrinsic apoptotic pathway by reducing the activation of JNK and Bax (Go et al 2021 ).…”

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