Oncotarget

Research Papers:

Exogenous pyruvate facilitates cancer cell adaptation to hypoxia by serving as an oxygen surrogate

Chengqian Yin, Dan He, Shuyang Chen, Xiaoling Tan and Nianli Sang _

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Oncotarget. 2016; 7:47494-47510. https://doi.org/10.18632/oncotarget.10202

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Abstract

Chengqian Yin1, Dan He1, Shuyang Chen1,4, Xiaoling Tan2, Nianli Sang1,3

1Department of Biology, Drexel University College of Arts and Sciences, Philadelphia, Pennsylvania, USA

2Department of High Altitude Physiology, the Third Military Medical University, Chongqing, China

3Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

4Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA

Correspondence to:

Nianli Sang, email: [email protected]

Keywords: ATP, hypoxia, metabolism, pyruvate, NAD+

Received: March 30, 2016     Accepted: June 09, 2016     Published: June 21, 2016

ABSTRACT

Molecular oxygen is the final electron acceptor in cellular metabolism but cancer cells often become adaptive to hypoxia, which promotes resistance to chemotherapy and radiation. The reduction of endogenous glycolytic pyruvate to lactate is known as an adaptive strategy for hypoxic cells. Whether exogenous pyruvate is required for hypoxic cell proliferation by either serving as an electron acceptor or a biosynthetic substrate remains unclear. By using both hypoxic and ρ0 cells defective in electron transfer chain, we show that exogenous pyruvate is required to sustain proliferation of both cancer and non-cancer cells that cannot utilize oxygen. Particularly, we show that absence of pyruvate led to glycolysis inhibition and AMPK activation along with decreased NAD+ levels in ρ0 cells; and exogenous pyruvate increases lactate yield, elevates NAD+/NADH ratio and suppresses AMPK activation. Knockdown of lactate dehydrogenase significantly inhibits the rescuing effects of exogenous pyruvate. In contrast, none of pyruvate-derived metabolites tested (including acetyl-CoA, α-ketoglutarate, succinate and alanine) can replace pyruvate in supporting ρ0 cell proliferation. Knockdown of pyruvate carboxylase, pyruvate dehydrogenase and citrate synthase do not impair exogenous pyruvate to rescue ρ0 cells. Importantly, we show that exogenous pyruvate relieves ATP insufficiency and mTOR inhibition and promotes proliferation of hypoxic cells, and that well-oxygenated cells release pyruvate, providing a potential in vivo source of pyruvate. Taken together, our data support a novel pyruvate cycle model in which oxygenated cells release pyruvate for hypoxic cells as an oxygen surrogate. The pyruvate cycle may be targeted as a new therapy of hypoxic cancers.


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