Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Author L Jin, J Chun, C Pan, G Alesi, D Li, K Magliocca, Y Kang, Z Chen, D Shin, F Khuri, J Fan, S Kang Publication Year 2017 Type Journal Article Abstract 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. Keywords Animals, Humans, Cell Proliferation, Phosphorylation, Enzyme Activation, Protein Processing, Post-Translational, Female, Cell Line, Tumor, Breast Neoplasms, Isoenzymes, Lymphatic Metastasis, Receptor, ErbB-2, Antineoplastic Agents, Reactive Oxygen Species, Anoikis, Mice, Nude, Neoplasm Invasiveness, Neoplasm Transplantation, L-Lactate Dehydrogenase, Benzodioxoles, Lactate Dehydrogenase 5, Quinazolines, src-Family Kinases Journal Oncogene Volume 36 Issue 27 Pages 3797-3806 Date Published 2017 Jul 06 ISSN Number 1476-5594 DOI 10.1038/onc.2017.6 Alternate Journal Oncogene PMCID PMC5501759 PMID 28218905 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML