title: Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis.
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.
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chun
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pan
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Alesi
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Magliocca
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Z G
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: F R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Winship Cancer Institute, Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fan
authors.affiliation: Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kang
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008207:Lymphatic Metastasis; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011799:Quinazolines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D011799:Quinazolines; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D019061:src-Family Kinases; C515233:saracatinib; C508053:ERBB2 protein, human