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Published, Version of Record (VoR)CC BY V4.0, Open
Journal article
Exogenous pyruvate facilitates cancer cell adaptation to hypoxia by serving as an oxygen surrogate
Oncotarget, v 7(30), pp 47494-47510
26 Jul 2016
PMID: 27374086
Featured in Collection : UN Sustainable Development Goals @ Drexel
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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Details
- Title
- Exogenous pyruvate facilitates cancer cell adaptation to hypoxia by serving as an oxygen surrogate
- Creators
- Chengqian Yin - Department of Biology, Drexel University College of Arts and Sciences, Philadelphia, Pennsylvania, USA.Dan He - Department of Biology, Drexel University College of Arts and Sciences, Philadelphia, Pennsylvania, USA.Shuyang Chen - Department of Biology, Drexel University College of Arts and Sciences, Philadelphia, Pennsylvania, USA.Xiaoling Tan - Army Medical UniversityNianli Sang - Drexel University
- Publication Details
- Oncotarget, v 7(30), pp 47494-47510
- Grant note
- R01 CA129494 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000385413000052
- Scopus ID
- 2-s2.0-84982843550
- Other Identifier
- 991019167884304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Oncology