Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter

Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasi...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2017-10, Vol.77 (20), p.5591-5601
Main Authors: Payen, Valéry L, Hsu, Myriam Y, Rädecke, Kristin S, Wyart, Elisabeth, Vazeille, Thibaut, Bouzin, Caroline, Porporato, Paolo E, Sonveaux, Pierre
Format: Article
Language:English
Subjects:
Acidosis
Animals
Biological Transport
Cancer
Cell adhesion & migration
Cell Line, Tumor
Cell migration
Cell Movement - physiology
Clonal deletion
Enzymes
Extracellular matrix
Female
Homeostasis
Humans
Hydrogen ions
Inhibition
Lactic acid
Mammary Neoplasms, Experimental - metabolism
Mammary Neoplasms, Experimental - pathology
Metastases
Metastasis
Mice
Mice, Inbred BALB C
Migration
Monocarboxylic Acid Transporters - metabolism
Neoplasm Invasiveness
Neoplasm Metastasis
NF-κB protein
pH effects
Proteolysis
Proteolytic enzymes
Symporters - metabolism
Tumors
Uterine Cervical Neoplasms - metabolism
Uterine Cervical Neoplasms - pathology
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Summary:Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-17-0764