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.

AMPK/GSK3β/β‐catenin cascade‐triggered overexpression of CEMIP promotes migration and invasion in anoikis‐resistant prostate cancer cells by enhancing metabolic reprogramming

“…Lactate dehydrogenase has 2 subunits that contained an enzyme that catalyzes the interconversion between pyruvate and lactate, and LDHA is mostly responsible for anaerobic and pyruvate metabolism. Up-regulation of PDK4 or LDHA ensures efficient glycolysis for tumor cells, which is believed to play an important role in anoikis resistance, invasion, and metastasis in human cancer (47)(48)(49). Similarly, increased expression of PDK4 and LDHA has also been confirmed in PCa and might be associated with tumor progression (50,51).…”

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

“…Moreover it has been reported that it promotes cancer cell invasion, anoikis resistance and tumor metastasis, via HER2 and Src pathways [43,44]. It has also been demonstrated that an experimentally increased expression of 14-3-3ζ in human mammary epithelial cells up-regulates LDHA expression, elevates glycolytic activity, and promotes early transformation through the MEK-ERK-CREB axis [45].…”

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

“…Phosphorylation significantly increased enzymatic activity of LDHA, which is associated with cancer progression. In breast cancer, Jin et al revealed that Y10 phosphorylation elicited LDHA activation, promoting cancer cell invasion and enhancing anoikis resistance. Also in colorectal cancer, Ji et al found that human coilin–interacting nuclear ATPase protein (hCINAP) expression was positively correlated with the level of Y10 phosphorylated LDHA.…”