title: Exogenous pyruvate facilitates cancer cell adaptation to hypoxia by serving as an oxygen surrogate.
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.
authors.affiliation: Department of Biology, Drexel University College of Arts and Sciences, Philadelphia, Pennsylvania, USA.
authors.forename: Chengqian
authors.initials: C
authors.lastname: Yin
authors.affiliation: Department of Biology, Drexel University College of Arts and Sciences, Philadelphia, Pennsylvania, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Biology, Drexel University College of Arts and Sciences, Philadelphia, Pennsylvania, USA.|Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of High Altitude Physiology, the Third Military Medical University, Chongqing, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Biology, Drexel University College of Arts and Sciences, Philadelphia, Pennsylvania, USA.|Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Nianli
authors.initials: N
authors.lastname: Sang
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000222:Adaptation, Physiological; D000255:Adenosine Triphosphate / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004579:Electron Transport; D006019:Glycolysis; D006801:Humans; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy; D062907:Oxaloacetic Acid / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D019289:Pyruvic Acid / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D009243:NAD; D062907:Oxaloacetic Acid; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen
keywords: ATP; NAD+; hypoxia; metabolism; pyruvate