title: Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD(+) redox homeostasis in cancer cells.
abstract: The Warburg effect describes an increase in aerobic glycolysis and enhanced lactate production in cancer cells. Lactate dehydrogenase A (LDH-A) regulates the last step of glycolysis that generates lactate and permits the regeneration of NAD(+). LDH-A gene expression is believed to be upregulated by both HIF and Myc in cancer cells to achieve increased lactate production. However, how oncogenic signals activate LDH-A to regulate cancer cell metabolism remains unclear. We found that the oncogenic receptor tyrosine kinase FGFR1 directly phosphorylates LDH-A. Phosphorylation at Y10 and Y83 enhances LDH-A activity by enhancing the formation of active, tetrameric LDH-A and the binding of LDH-A substrate NADH, respectively. Moreover, Y10 phosphorylation of LDH-A is common in diverse human cancer cells, which correlates with activation of multiple oncogenic tyrosine kinases. Interestingly, cancer cells with stable knockdown of endogenous LDH-A and rescue expression of a catalytic hypomorph LDH-A mutant, Y10F, demonstrate increased respiration through mitochondrial complex I to sustain glycolysis by providing NAD(+). However, such a compensatory increase in mitochondrial respiration in Y10F cells is insufficient to fully sustain glycolysis. Y10 rescue cells show decreased cell proliferation and ATP levels under hypoxia and reduced tumor growth in xenograft nude mice. Our findings suggest that tyrosine phosphorylation enhances LDH-A enzyme activity to promote the Warburg effect and tumor growth by regulating the NADH/NAD(+) redox homeostasis, representing an acute molecular mechanism underlying the enhanced lactate production in cancer cells.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.forename: Taro
authors.initials: T
authors.lastname: Hitosugi
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xie
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Ge
authors.forename: Ting-Lei
authors.initials: TL
authors.lastname: Gu
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Polakiewicz
authors.forename: Georgia Z
authors.initials: GZ
authors.lastname: Chen
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Sumin
authors.initials: S
authors.lastname: Kang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019069:Cell Respiration; D006019:Glycolysis; D006706:Homeostasis; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D009243:NAD; D019344:Lactic Acid; D014443:Tyrosine; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D051496:Receptor, Fibroblast Growth Factor, Type 1