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 MCT1 in vivo 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

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

Hsu, Myriam;Wyart, Elisabeth;Porporato, Paolo E.;Sonveaux, Pierre
2017

Abstract

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 MCT1 in vivo 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
77
20
5591
5601
http://cancerres.aacrjournals.org/content/77/20/5591.full-text.pdf
Animals; Biological Transport; Cell Line, Tumor; Cell Movement; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Monocarboxylic Acid Transporters; Neoplasm Invasiveness; Neoplasm Metastasis; Symporters; Uterine Cervical Neoplasms; Oncology; Cancer Research
Payen, Valéry L.; Hsu, Myriam; Rädecke, Kristin S.; Wyart, Elisabeth; Vazeille, Thibaut; Bouzin, Caroline; Porporato, Paolo E.; Sonveaux, Pierre*
File in questo prodotto:
File Dimensione Formato  
44 Payen et al 2017 Cancer Research (1).pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 1.84 MB
Formato Adobe PDF
1.84 MB Adobe PDF Visualizza/Apri
pubb 3.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 2.38 MB
Formato Adobe PDF
2.38 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1661661
Citazioni
  • ???jsp.display-item.citation.pmc??? 41
  • Scopus 70
  • ???jsp.display-item.citation.isi??? 68
social impact