Monocarboxylate Transporter 4 Facilitates Cell Proliferation and Migration and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma Patients

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Abstract

Monocarboxylate transporter 4 (MCT4) is a cell membrane transporter of lactate. Recent studies have shown that MCT4 is over-expressed in various cancers; however, its role in cancer maintenance and aggressiveness has not been fully demonstrated. This study investigated the role of MCT4 in oral squamous cell carcinoma (OSCC), and found that it is highly expressed in OSCC patients by using immunohistochemistry. Moreover, this over-expression of MCT4 was closely associated with tumor size, TNM classification, lymphatic metastasis, distant metastasis and tumor recurrence, and also poor prognosis. To further study mechanisms of MCT4 in vitro, we used small-interfering RNA to silence its expression in OSCC cell lines. The results showed that knock-down of MCT4 decreased cell proliferation, migration, and invasion. The inhibition of proliferation was associated with down-regulation of p-AKT and p-ERK1/2, while decreased cell migration and invasion may be caused by down-regulation of integrin β4-SRC-FAK and MEK-ERK signaling. Together, these findings provide new insight into the critical role of MCT4 in cell proliferation and metastasis in OSCC.

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Most cited references 34

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FAK integrates growth-factor and integrin signals to promote cell migration.

D J Sieg, C Hauck, D Ilic … (2000)

Here we show that cells lacking focal adhesion kinase (FAK) are refractory to motility signals from platelet-derived and epidermal growth factors (PDGF and EGF respectively), and that stable re-expression of FAK rescues these defects. FAK associates with activated PDGF- and EGF-receptor (PDGFR and EGFR) signalling complexes, and expression of the band-4.1-like domain at the FAK amino terminus is sufficient to mediate an interaction with activated EGFR. However, efficient EGF-stimulated cell migration also requires FAK to be targeted, by its carboxy-terminal domain, to sites of integrin-receptor clustering. Although the kinase activity of FAK is not needed to promote PDGF- or EGF-stimulated cell motility, kinase-inactive FAK is transphosphorylated at the indispensable Src-kinase-binding site, FAK Y397, after EGF stimulation of cells. Our results establish that FAK is an important receptor-proximal link between growth-factor-receptor and integrin signalling pathways.

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Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells.

Olivier Feron (2009)

Tumor cells fuel their metabolism with glucose and glutamine to meet the bioenergetic and biosynthetic demands of proliferation. Hypoxia and oncogenic mutations drive glycolysis, with the pyruvate to lactate conversion being promoted by increased expression of lactate dehydrogenase A and inactivation of pyruvate dehydrogenase. The NAD+ pool is consecutively regenerated and supports the high glycolytic flux required to produce anabolic intermediates. Glutaminolysis provides metabolic intermediates such as alpha-ketoglutarate to feed and thereby maintain the tricarboxylic acid cycle as a biosynthetic hub. Glycolysis and glutaminolysis share the capacity to generate NADPH, from the pentose phosphate pathway and through the malate conversion into pyruvate, respectively. Both pathways ultimately lead to the secretion of lactate. More than a waste product, lactate was recently identified as a major energy fuel in tumors. Lactate produced by hypoxic tumor cells may indeed diffuse and be taken up by oxygenated tumor cells. Preferential utilization of lactate for oxidative metabolism spares glucose which may in turn reach hypoxic tumor cells. Monocarboxylate transporter 1 regulates the entry of lactate into oxidative tumor cells. Its inhibition favors the switch from lactate-fuelled respiration to glycolysis and consecutively kills hypoxic tumor cells from glucose starvation. Combination with radiotherapy renders remaining cells more sensitive to irradiation, emphasizing how interference with tumor cell metabolism may complement current anticancer modalities.

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The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells.

S L Broer, Kai Dimmer, Frederick F. Lang … (2000)

Transport of lactate and other monocarboxylates in mammalian cells is mediated by a family of transporters, designated monocarboxylate transporters (MCTs). The MCT4 member of this family has recently been identified as the major isoform of white muscle cells, mediating lactate efflux out of glycolytically active myocytes [Wilson, Jackson, Heddle, Price, Pilegaard, Juel, Bonen, Montgomery, Hutter and Halestrap (1998) J. Biol. Chem. 273, 15920-15926]. To analyse the functional properties of this transporter, rat MCT4 was expressed in Xenopus laevis oocytes and transport activity was monitored by flux measurements with radioactive tracers and by changes of the cytosolic pH using pH-sensitive microelectrodes. Similar to other members of this family, monocarboxylate transport via MCT4 is accompanied by the transport of H(+) across the plasma membrane. Uptake of lactate strongly increased with decreasing extracellular pH, which resulted from a concomitant drop in the K(m) value. MCT4 could be distinguished from the other isoforms mainly in two respects. First, MCT4 is a low-affinity MCT: for L-lactate K(m) values of 17+/-3 mM (pH-electrode) and 34+/-5 mM (flux measurements with L-[U-(14)C]lactate) were determined. Secondly, lactate is the preferred substrate of MCT4. K(m) values of other monocarboxylates were either similar to the K(m) value for lactate (pyruvate, 2-oxoisohexanoate, 2-oxoisopentanoate, acetoacetate) or displayed much lower affinity for the transporter (beta-hydroxybutyrate and short-chain fatty acids). Under physiological conditions, rat MCT will therefore preferentially transport lactate. Monocarboxylate transport via MCT4 could be competitively inhibited by alpha-cyano-4-hydroxycinnamate, phloretin and partly by 4, 4'-di-isothiocyanostilbene-2,2'-disulphonic acid. Similar to MCT1, monocarboxylate transport via MCT4 was sensitive to inhibition by the thiol reagent p-chloromercuribenzoesulphonic acid.

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Author and article information

Contributors

Chih-Hsin Tang: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 30 January 2014

Volume: 9

Issue: 1

Electronic Location Identifier: e87904

Affiliations

[1 ]Institute of Stomatology, Nanjing Medical University, Nanjing, PR China

[2 ]Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Jiangsu Province, Nanjing, PR China

[3 ]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, China Academy of Sciences, Shanghai, China

China Medical University, Taiwan

Author notes

* E-mail: xiezuoquan@ 123456mail.shcnc.ac.cn (ZQX); whmz2002zj@ 123456126.com (HMW)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: YNW MYG ZQX HMW. Performed the experiments: JZ. Analyzed the data: HMW JZ. Contributed reagents/materials/analysis tools: WZ XMZ XD HQL. Wrote the paper: JZ ZQX.

Article

Publisher ID: PONE-D-13-42745

DOI: 10.1371/journal.pone.0087904

PMC ID: 3907573

PubMed ID: 24498219

SO-VID: efd040f4-119e-47aa-b3c6-bf51286b98f4

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 21 October 2013

Date accepted : 30 December 2013

Page count

Pages: 11

Funding

This work was supported by National Natural Science Foundation of China (NO. 81202549), National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2012ZX09301001-007), and by Priority Academic Program Development of Jiangsu Higher Education Institutions (No. jx10531801/005).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Monocarboxylate Transporter 4 Facilitates Cell Proliferation and Migration and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma Patients

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Most cited references 34

FAK integrates growth-factor and integrin signals to promote cell migration.

Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells.

The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells.

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