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Abstract 2802: Exogenous pyruvate supports oxygen-independent tumor cell proliferation by serving as an oxygen surrogate to maintain homeostasis of NAD+/NADH
Journal article   Peer reviewed

Abstract 2802: Exogenous pyruvate supports oxygen-independent tumor cell proliferation by serving as an oxygen surrogate to maintain homeostasis of NAD+/NADH

Chengqian Yin, Dan He, Shuyang Chen and Nianli Sang
Cancer research (Chicago, Ill.), v 76(14_Supplement), pp 2802-2802
15 Jul 2016
DOI: https://doi.org/10.1158/1538-7445.AM2016-2802

Abstract

Abstract Hypoxia is usually associated with solid tumors and ischemic lesions. Because oxygen is the common final electron acceptor in a variety of metabolic reactions, hypoxia leads to cell injury and death in normal tissues but promotes tumor progression and metastasis. Hypoxic cells use pyruvate from glycolysis as electron acceptor to support ATP production; anaerobic glycolysis, in which the glycolytic product pyruvate is converted to lactate, has been well established as an adaptive energy strategy for hypoxic cells. In tumor cells, pyruvate may also be used as a substrate to support an active biosynthesis, as well as to maintain the homeostasis of NAD+/NAD. However, whether exogenous pyruvate promotes hypoxic tumor cell proliferation by serving as an electron acceptor or a biosynthetic substrate remains unclear. By using both hypoxia and ρ0 cell with defective mitochondrial electron transfer chain, we show that exogenous pyruvate sustains the proliferation of tumor cells that cannot use oxygen as the electron acceptor. Pyruvate-derived metabolites including acetyl-coA, α-ketoglutarate, succinate, alanine, and aspartate were not able to substitute pyruvate to support oxygen-independent proliferation. Knockdown of metabolic enzymes including pyruvate carboxylase, pyruvate dehydrogenase and citrate synthetase showed no negative effects on pyruvate-facilitated hypoxic cell proliferation, whereas knockdown of lactate dehydrogenase significantly inhibited proliferation, indicating that the crucial role of exogenous pyruvate is to serve as the electron acceptor other than a substrate for proliferating biosynthesis. Consisting with this notion, we show that exogenous pyruvate significantly increased lactate generation and increased the ratio of NAD+/NADH. We also show that in our model cells, hypoxia did not cause accumulation of reactive oxygen species, suggesting that pyruvate-facilitated proliferation of hypoxic cells is not achieved by alleviating oxidative stress. Finally, we show that well-oxygenated cells release pyruvate, providing an in vivo source of pyruvate exogenous to the hypoxic cells. Taken together, our data support a novel model that well-oxygenated cells release pyruvate, which is utilized by hypoxic cells as an electron acceptor to facilitate proliferation. This model provides a potential new therapeutic target to suppress tumor progression. Citation Format: Chengqian Yin, Dan He, Shuyang Chen, Nianli Sang. Exogenous pyruvate supports oxygen-independent tumor cell proliferation by serving as an oxygen surrogate to maintain homeostasis of NAD+/NADH. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2802.

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