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.

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Acknowledgements

We thank Dr Anthea Hammond for editing the manuscript. We acknowledge the Winship shared resources facilities. 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. Gina N. Alesi is an NIH pre-doctoral fellow. Sumin Kang is an American Cancer Society Basic Research Scholar, a Robbins Scholar, and a Georgia Cancer Coalition Scholar. Grant Support: This work was supported by NIH grants R01 CA175316 (Sumin Kang), F31 CA183365 (Gina N. Alesi), and ACS grant RSG-11-08101 (Sumin Kang).

Author contributions

YK, DMS, ZGC and FRK provided critical reagents. KRM conducted histopathological analysis. JF performed crosslinking assay and LDH activity assay. LJ, JC, GNA and DL conducted the other experiments. SK and LJ were responsible for the study design and wrote the paper.

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Correspondence to S Kang.

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Jin, L., Chun, J., Pan, C. et al. Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene 36, 3797–3806 (2017). https://doi.org/10.1038/onc.2017.6

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