Monocarboxylate transporter 1 (MCT1) promotes tumor metastasis independently of its activity as a transporter of lactate

Metastasis is of poor prognosis for cancer patients as it marks the transition between a localized and a systemic disease, thus limiting therapeutic opportunities for cancer cure. Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion and metastasis. While host cells die at low extracellular pH, cancer cells are more resistant as they are well equipped with transporters and enzymes that regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Among proton transporters, monocarboxylate transporter 1 (MCT1) is a passive transporter of lactic acid that could constitute an interesting target for metastatic prevention: several lines of evidence indicate that MCT1 promotes cancer cell migration and invasion, and MCT1 inhibitor AZD3965 recently entered Phase I/II clinical trials. Because MCT1 is usually described as an inward transporter of lactic acid in cancer, we addressed the mechanism by which MCT1 could possibly contribute to the metastatic process. We report that MCT1 activates transcription factor NF-κB, which promotes cancer cell migration independently of MCT1 activity as a transporter. While pharmacological MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, MCT1 silencing or its genetic deletion inhibited migration, invasion and spontaneous metastasis in vivo. Therefore, pharmacological agents that inhibit the transport of lactic acid by MCT1 would not prevent metastatic dissemination of cancer cells.