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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 |
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| Main Authors: | , , , , , , , |
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| cites | cdi_FETCH-LOGICAL-c502t-c0fb085a3c8865b251b6296d3e7a3e47a342bd72d8458a40e13c679ca28f4083 |
| container_end_page | 5601 |
| container_issue | 20 |
| container_start_page | 5591 |
| container_title | Cancer research (Chicago, Ill.) |
| container_volume | 77 |
| creator | Payen, Valéry L Hsu, Myriam Y Rädecke, Kristin S Wyart, Elisabeth Vazeille, Thibaut Bouzin, Caroline Porporato, Paolo E Sonveaux, Pierre |
| description | 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.
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| doi_str_mv | 10.1158/0008-5472.can-17-0764 |
| format | article |
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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.
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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.
.</description><subject>Acidosis</subject><subject>Animals</subject><subject>Biological Transport</subject><subject>Cancer</subject><subject>Cell adhesion & migration</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - physiology</subject><subject>Clonal deletion</subject><subject>Enzymes</subject><subject>Extracellular matrix</subject><subject>Female</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Hydrogen ions</subject><subject>Inhibition</subject><subject>Lactic acid</subject><subject>Mammary Neoplasms, Experimental - metabolism</subject><subject>Mammary Neoplasms, Experimental - pathology</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Migration</subject><subject>Monocarboxylic Acid Transporters - metabolism</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Metastasis</subject><subject>NF-κB protein</subject><subject>pH effects</subject><subject>Proteolysis</subject><subject>Proteolytic enzymes</subject><subject>Symporters - metabolism</subject><subject>Tumors</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Uterine Cervical Neoplasms - pathology</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpdkU1LAzEQhoMotlZ_ghLw4mVrPjfpsRQ_Cq162HvIZrOwZXdTk6zYf29Kaw-FYYYZnnkZ5gXgHqMpxlw-I4RkxpkgU6P7DIsMiZxdgDHmVGaCMX4JxidmBG5C2KSWY8SvwYhISQQVZAy-1653RvvS_e5aHS0svO7D1vloPVwvCgy_vOtctAEWQ-fSzEYdUjQBLvvKbm1KfWx30NVwGQOcm9j8NHEHdYAarrSJZ6q34KrWbbB3xzoBxetLsXjPVp9vy8V8lRmOSMwMqkskuaZGypyXhOMyJ7O8olZoallKjJSVIJVkXGqGLKYmFzOjiawZknQCng6yW---Bxui6ppgbNvq3rohKDyjmNBcUJbQxzN04wbfp-MSJSlhguc8UfxAGe9C8LZWW9902u8URmpvidq_W-3frRbzD4WF2luS9h6O6kPZ2eq09e8B_QOrn4fQ</recordid><startdate>20171015</startdate><enddate>20171015</enddate><creator>Payen, Valéry L</creator><creator>Hsu, Myriam Y</creator><creator>Rädecke, Kristin S</creator><creator>Wyart, Elisabeth</creator><creator>Vazeille, Thibaut</creator><creator>Bouzin, Caroline</creator><creator>Porporato, Paolo E</creator><creator>Sonveaux, Pierre</creator><general>American Association for Cancer Research, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20171015</creationdate><title>Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter</title><author>Payen, Valéry L ; 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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.
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| 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 |
| title | Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter |
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