A role for lactate dehydrogenase in the c-Met/HGF signaling axis

Tumor cells often display a glycolytic phenotype, even in the presence of oxygen; a phenomenon known as the Warburg effect. The ability of cancerous cells to perform aerobic glycolysis is unique when compared to non-cancerous cells, and therefore, presents a possible therapeutic target for elimination of cancer cells that rely on aerobic glycolysis. Activation of the receptor tyrosine kinase, c-Met, by hepatocyte growth factor (HGF) is a major contributing event in the progression of prostate cancer (PCa). Signaling through this receptor leads to increased cell motility, proliferation, invasion and metastasis. Studies have shown that targeting this signaling axis can greatly reduce the number of bone metastases that arise from primary PCa tumors. Oxamate, a lactate dehydrogenase (LDH) inhibitor, and 2-deoxyglucose (2-DG) are known glycolytic inhibitors. Our studies have found that oxamate reduced c-Met activation and HGF-induced cell motility, while 2-DG had no effect. In order to confirm that oxamate was targeting LDH-A or LDH-B, we created LDH-A, LDH-B, and LDH-A/B knockdown (KD) DU145 cells. Although all of the clones used in the experiments had greater than 70% KD, we were unable to recapitulate the effects seen with oxamate. We believe that this could be due to incomplete KD. In support of this, use of a specific LDH-A (πFly-21) inhibitor significantly reduced c-Met activation and HGF-induced cell motility. Together, these data support a role for LDH-A in facilitating HGF-induced c-Met activation. Because oxamate is a direct LDH inhibitor, we hypothesized that oxamate would have a greater reduction in lactate (LA) export from cells than 2-DG; however, both, oxamate and 2-DG reduced LA production by approximately 75% in DU145 prostate cancer cells. Therefore, the ability of oxamate to reduce c-Met activation is not apparently due to a decrease in LA export. However, it is possible that LA import via monocarboxylate transporter 1 (MCT1) activity may be important for c-Met activation and downstream signaling events. In support of this, KD of MCT1 resulted in reduced c-Met activation and blocked HGF-induced cell motility. These data indicate a potential connection between LDH activity/lactate import and the c-Met signaling axis, suggesting that inhibition of these processes may be a new mechanism for preventing c-Met driven metastatic events.