Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis

• Type of Material: Article
• Authors: Lingtao Jin, Emory University; J Chun, Emory University; C Pan, Emory University; GN Alesi, Emory University; D Li, Emory University; Kelly Magliocca, Emory University; Y Kang, Princeton University; Georgia Chen, Emory University; Dong M Shin, Emory University; Fadlo Khuri, Emory University; Jun Fan, Emory University; Sumin Kang, Emory University
• Language: English
• Date: 2017-07-06
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Macmillan Publishers Limited, part of Springer Nature.
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2017.6
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 36
• Issue: 27
• Start Page: 3797
• End Page: 3806
• Grant/Funding Information: This work was supported by NIH grants R01 CA175316 (Sumin Kang), F31 CA183365 (Gina N. Alesi), ACS grant RSG-11-08101 (Sumin Kang) and Pilot Grant-2015/Winship Cancer Institute, Emory University.
• Keywords: Science & Technology; HEAD; SRC ACTIVATION; CARCINOMA; LACTATE-DEHYDROGENASE; METABOLISM; Cell Biology; PROGRESSION; REDOX HOMEOSTASIS; Oncology; DOWN-REGULATION; NECK-CANCER; Genetics & Heredity; TYROSINE PHOSPHORYLATION; Biochemistry & Molecular Biology; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology; Biology, Molecular

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.