Abstract 2798: Tyrosine phosphorylation of LDH-A is important for cancer cell redox homeostasis and tumor growth

Abstract

Abstract Cancer cells take up more glucose than normal tissue and favor aerobic glycolysis, generating lactate through a NADH-dependent enzyme, lactate dehydrogenase A (LDH-A). This is the last step of glycolysis that permits the regeneration of NAD+, which is needed as an electron acceptor to maintain cytosolic glucose catabolism. Therefore, most tumor cells are reliant on lactate production for their survival. LDH-A gene expression is believed to be upregulated by both HIF and Myc in cancer cells to achieve increased lactate production, and expression of LDH-A was previously implicated to be involved in tumour initiation and growth. However, how oncogenic signals activate LDH-A to regulate cancer cell metabolism remains unclear. Our phospho-proteomics studies revealed that oncogenic fibroblast growth factor (FGF) receptor type 1 (FGFR1) tyrosine kinase directly phosphorylates LDH-A. Structural and biochemical studies revealed that phosphorylation at Y10 and Y83 activates LDH-A by promoting the formation of active, tetrameric LDH-A and binding of LDH-A substrate NADH, respectively. Moreover, we found that LDH-A is commonly phosphorylated at Y10 in diverse human cancer cells by multiple oncogenic tyrosine kinases including BCR-ABL, FLT3 and JAK2, which represents an acute molecular mechanism underlying increased lactate production in cancer cells. Furthermore, cancer cells with stable knockdown of endogenous LDH-A and rescue expression of a catalytic hypomorph LDH-A mutant, Y10F, show decreased cell proliferation and ATP levels under hypoxia, increased mitochondrial respiration to sustain glycolysis by providing NAD+, and reduced tumor growth in xenograft nude mice. Our findings suggest that tyrosine phosphorylation activates LDH-A to promote the Warburg effect and tumor growth by regulating NADH/NAD+ redox homeostasis in cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2798. doi:10.1158/1538-7445.AM2011-2798