Metastases remain the major cause of death from
cancer. Recent molecular advances have highlighted the importance of metabolic alterations in
cancer cells, including the Warburg effect that describes an increased glycolysis in
cancer cells. However, how this altered metabolism contributes to tumour
metastasis remains elusive. Here, we report that phosphorylation-induced activation of
lactate dehydrogenase A (LDHA), an
enzyme that catalyses the interconversion of
pyruvate and
lactate, promotes
cancer cell invasion, anoikis resistance and tumour
metastasis. We demonstrate that LDHA is phosphorylated at
tyrosine 10 by upstream
kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in
head and neck cancer and
breast cancer cells. Inhibition of LDH activity by small hairpin
ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the
cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated
reactive oxygen species, whereas such phenotypes were reversed by its product
lactate or
antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes
cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human
cancer cells resulted in decreased tumour
metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic
breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to
cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human
cancers.