Expression of Monocarboxylate Transporters 1, 2, and 4 in Human Tumours and Their Association with CD147 and CD44

Pinheiro, Céline; Reis, Rui Manuel; Ricardo, Sara; Longatto‐Filho, Adhemar; Schmitt, Fernando; Baltazar, Fátima

doi:10.1155/2010/427694

Cited by 147 publications

(146 citation statements)

References 40 publications

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“…Previous studies have found greater ENT1 mRNA expression in breast cancer than in cancer cell lines derived from stomach cancer (Lu et al, 2002;Kameyama et al, 2011). Immunohistochemical analysis showed that the frequency of MCT1 expression was greater in human stomach cancer tissues than in breast cancer tissues (Pinheiro et al, 2009(Pinheiro et al, , 2010. These transporter expression profiles are consistent with the present results.…”

Section: Discussionsupporting

confidence: 92%

Identification of Transporters Associated with Etoposide Sensitivity of Stomach Cancer Cell Lines and Methotrexate Sensitivity of Breast Cancer Cell Lines by Quantitative Targeted Absolute Proteomics

Obuchi

Ohtsuki²,

Uchida

et al. 2013

Molecular Pharmacology

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Membrane transporter proteins may influence the sensitivity of cancer cells to anticancer drugs that can be recognized as substrates. The purpose of this study was to identify proteins that play a key role in the drug sensitivity of stomach and breast cancer cell lines by measuring the absolute protein expression levels of multiple transporters and other membrane proteins and examining their correlation to drug sensitivity. Absolute protein expression levels of 90 membrane proteins were examined by quantitative targeted absolute proteomics using liquid chromatography-linked tandem mass spectrometry. Among them, 11 and 14 membrane proteins, including transporters, were present in quantifiable amounts in membrane fraction of stomach cancer and breast cancer cell lines, respectively. In stomach cancer cell lines, the protein expression level of multidrug resistance-associated protein 1 (MRP1) was inversely correlated with etoposide sensitivity. MK571, an MRP inhibitor, increased both the cell-to-medium ratio of etoposide and the etoposide sensitivity of MRP1-expressing stomach cancer cell lines. In breast cancer cell lines, the protein expression level of reduced folate carrier 1 (RFC1) was directly correlated with methotrexate (MTX) sensitivity. Initial uptake rate and steady-state cell-to-medium ratio of [ 3 H]MTX were correlated with both RFC1 expression level and MTX sensitivity. These results suggest that MRP1 modulates the etoposide sensitivity of stomach cancer cell lines and RFC1 modulates the MTX sensitivity of breast cancer cell lines. Our results indicate that absolute quantification of multiple membrane proteins could be a useful strategy for identification of candidate proteins involved in drug sensitivity.

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Section: Discussionsupporting

confidence: 92%

Identification of Transporters Associated with Etoposide Sensitivity of Stomach Cancer Cell Lines and Methotrexate Sensitivity of Breast Cancer Cell Lines by Quantitative Targeted Absolute Proteomics

Obuchi

Ohtsuki²,

Uchida

et al. 2013

Molecular Pharmacology

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“…49 Immunohistochemistry for MCT4, GLUT1, and CAIX was performed according to the streptavidin-biotin-peroxidase complex principle (Ultravision Detection System Anti-polyvalent, HRP, Thermo Scientific, #TP-125-HL), as previously described. [50][51][52] Specificity of the antibodies was previously validated by siRNA followed by Western-blot. 53,54 Negative controls were performed by the use of appropriate serum controls for the primary antibodies (Dako, #N1698 and #N1699).…”

Section: Immunohistochemistrymentioning

confidence: 99%

The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4

et al. 2016

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BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.

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“…Both MCT1 and MCT4 were found in cancer cells, closely associated with CD147, also known as Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) or basigin, a chaperone needed for the correct targeting of MCT1 and MCT4 to the cell surface and for their activity (Izumi et al 2003;Halestrap 2011;Nabeshima et al 2006;Riethdorf et al 2006;Hussien and Brooks 2011;Kirk et al 2000;Wilson et al 2005). Although these transporters are present in the plasma membrane of normal cells, there is evidence for their upregulation in cancer cells, given the increased lactic acid production and consequent efflux by the cell (Froberg et al 2001;Fang et al 2006;Pinheiro et al 2008a;Pinheiro et al 2008b;Pinheiro et al 2010a;Pinheiro et al 2010b). Tumor cells take up or export lactate according to the oxygen availability, lactate concentration and expression of the MCT subtype at the plasma membrane (Brooks 2000;Semenza 2008).…”

Section: Introductionmentioning

confidence: 99%

Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate

Queirós

Preto

Pacheco

et al. 2012

J Bioenerg Biomembr

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Most malignant tumors exhibit the Warburg effect, which consists in increased glycolysis rates with production of lactate, even in the presence of oxygen. Monocarboxylate transporters (MCTs), maintain these glycolytic rates, by mediating the influx and/or efflux of lactate and are overexpressed in several cancer cell types. The lactate and pyruvate analogue 3-bromopyruvate (3-BP) is an inhibitor of the energy metabolism, which has been proposed as a specific antitumor agent. In the present study, we aimed at determining the effect of 3-BP in breast cancer cells and evaluated the putative role of MCTs on this effect. Our results showed that the three breast cancer cell lines used presented different sensitivities to 3-BP: ZR-75-1 ER (+)>MCF-7 ER (+)>SK-BR-3 ER (-). We also demonstrated that 3-BP reduced lactate production, induced cell morphological alterations and increased apoptosis. The effect of 3-BP appears to be cytotoxic rather than cytostatic, as a continued decrease in cell viability was observed after removal of 3-BP. We showed that pre-incubation with butyrate enhanced significantly 3-BP cytotoxicity, especially in the most resistant breast cancer cell line, SK-BR-3. We observed that butyrate treatment induced localization of MCT1 in the plasma membrane as well as overexpression of MCT4 and its chaperone CD147. Our results thus indicate that butyrate pre-treatment potentiates the effect of 3-BP, most probably by increasing the rates of 3-BP transport through MCT1/4. This study supports the potential use of butyrate as adjuvant of 3-BP in the treatment of breast cancer resistant cells, namely ER (-).

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Expression of Monocarboxylate Transporters 1, 2, and 4 in Human Tumours and Their Association with CD147 and CD44

Cited by 147 publications

References 40 publications

Identification of Transporters Associated with Etoposide Sensitivity of Stomach Cancer Cell Lines and Methotrexate Sensitivity of Breast Cancer Cell Lines by Quantitative Targeted Absolute Proteomics

Identification of Transporters Associated with Etoposide Sensitivity of Stomach Cancer Cell Lines and Methotrexate Sensitivity of Breast Cancer Cell Lines by Quantitative Targeted Absolute Proteomics

The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4

Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate

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