Research Progress of The Monocarboxylate Transporter Proteins in Malignant Tumors_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 TANGShi-lei , YANGZhao-guo ,  LIHang-yu

Department of General Surgery, Affiliated Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China;

Corresponding author：

LIHang-yu, Email: li_hangyu@126.com

Keywords：

Monocarboxylate transporter proteins; Neoplasm; Metabolism; Warburg effects

DOI：

10.7507/1007-9424.20150195

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the latest research advance of monocarboxylate transporter proteins in malignant tumors in recent years. Methods Literatures about the recent studies on the regulation of monocarboxylate transporter proteins and the regulation of bioenergetic metabolic mechanisms in malignant tumors were reviewed according to the literatures searched from domestic and foreign databases. Results The abnormal high expression of the monocarboxylate transporter proteins existed in most of tumor cells' membrane, which endowed tumor cells high glycolysis rate and acid resistant phenotype, providing theoretical proofs for study of malignant biological behavior and therapeutic target of cancer cells. Conclusions The studies about the regulation of monocarboxylate transporter proteins on tumors' microenvironment and bioenergetic metabolism provide important clues for solving the mechanism of malignant biological behavior of tumor cells which based on abnormal bioenergetic metabolism. in this point, they also provide an opportunity for cancer treatment and are likely to become a new hotspot in cancer treatment.

Citation： TANGShi-lei, YANGZhao-guo, LIHang-yu. Research Progress of The Monocarboxylate Transporter Proteins in Malignant Tumors. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(6): 746-753. doi: 10.7507/1007-9424.20150195 Copy

1.	Halestrap AP, Meredith D.The SLC16 gene family-from monocarboxylate transporters(MCTs)to aromatic amino acid transporters and beyond.Pflugers Arch, 2004, 447(5):619-628.
2.	Halestrap AP.The SLC16 gene family-structure, role and regulation in health and disease.Mol Aspects Med, 2013, 34(2-3):337-349.
3.	Pinheiro C, Longatto-Filho A, Azevedo-Silva J, et al.Role of monocarboxylate transporters in human cancers:state of the art.J Bioenerg Biomembr, 2012, 44(1):127-139.
4.	Halestrap AP.The monocarboxylate transporter family-structure and functional characterization.IUBMB Life, 2012, 64(1):1-9.
5.	Halestrap AP, Price NT.The proton-linked monocarboxylate transporter(MCT)family:structure, function and regulation.Biochem J, 1999, 343 Pt 2:281-299.
6.	Pinheiro C, Sousa B, Albergaria A, et al.GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression.Histol Histopathol, 2011, 26(10):1279-1286.
7.	Gatenby RA, Gillies RJ.Why do cancers have high aerobic glycolysis?.Nat Rev Cancer, 2004, 4(11):891-899.
8.	Frauwirth KA, Thompson CB.Regulation of T lymphocyte metabolism.J Immunol, 2004, 172(8):4661-4665.
9.	Fischer K, Hoffmann P, Voelkl S, et al.Inhibitory effect of tumor cell-derived lactic acid on human T cells.Blood, 2007, 109(9):3812-3819.
10.	Végran F, Boidot R, Michiels C, et al.Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis.Cancer Res, 2011, 71(7):2550-2560.
11.	Ritzhaupt A, Wood IS, Ellis A, et al.Identification of a monocarboxylate transporter isoform type 1(MCT1)on the luminal membrane of human and pig colon.Biochem Soc Trans, 1998, 26(2):S120.
12.	Pinheiro C, Longatto-Filho A, Scapulatempo C, et al.Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas.Virchows Arch, 2008, 452(2):139-146.
13.	Koukourakis MI, Giatromanolaki A, Harris AL, et al.Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas:a metabolic survival role for tumor-associated stroma.Cancer Res, 2006, 66(2):632-637.
14.	Asada K, Miyamoto K, Fukutomi T, et al.Reduced expression of GNA11 and silencing of MCT1 in human breast cancers.Oncology, 2003, 64(4):380-388.
15.	Pinheiro C, Albergaria A, Paredes J, et al.Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma.Histopathology, 2010, 56(7):860-867.
16.	Pinheiro C, Reis RM, Ricardo S, et al.Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44.J Biomed Biotechnol, 2010, 2010:427694.
17.	Martins D, Beça FF, Sousa B, et al.Loss of caveolin-1 and gain of MCT4 expression in the tumor stroma key events in the progression from an in situ to an invasive breast carcinoma.Cell Cycle, 2013, 12(16):2684-2690.
18.	Hussien R, Brooks GA.Mitochondrial and plasma membrane lactate transporter and lactate dehydrogenase isoform expression in breast cancer cell lines.Physiol Genomics, 2011, 43(5):255-264.
19.	Froberg MK, Gerhart DZ, Enerson BE, et al.Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues.Neuroreport, 2001, 12(4):761-765.
20.	Mathupala SP, Parajuli P, Sloan AE.Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma:an in vitro study.Neurosurgery, 2004, 55(6):1410-1419.
21.	21王晓澍.CD147、MCT1在人脑胶质瘤中的表达及CD147单抗对U251细胞代谢干预的实验研究.四川:四川大学, 2006.
22.	Fang J, Quinones QJ, Holman TL, et al.The H⁺-linked monocarboxylate transporter(MCT1/SLC16A1):a potential therapeutic target for high-risk neuroblastoma.Mol Pharmacol, 2006, 70(6):2108-2115.
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24.	Miranda-Gonçalves V, Honavar M, Pinheiro C, et al.Monocarboxylate transporters(MCTs)in gliomas:expression and exploitation as therapeutic targets.Neuro Oncol, 2013, 15(2):172-188.
25.	Koukourakis MI, Giatromanolaki A, Bougioukas G, et al.Lung cancer:a comparative study of metabolism related protein expression in cancer cells and tumor associated stroma.Cancer Biol Ther, 2007, 6(9):1476-1479.
26.	Ladanyi M, Antonescu CR, Drobnjak M, et al.The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147.Am J Pathol, 2002, 160(4):1215-1221.
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28.	Pinheiro C, Longatto-Filho A, Pereira SM, et al.Monocarboxylate transporters 1 and 4 are associated with CD147 in cervical carcinoma.Dis Markers, 2009, 26(3):97-103.
29.	Pinheiro C, Longatto-Filho A, Ferreira L, et al.Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma.Int J Gynecol Pathol, 2008, 27(4):568-574.
30.	Chen H, Wang L, Beretov J, et al.Co-expression of CD147/EMMPRIN with monocarboxylate transporters and multiple drug resistance proteins is associated with epithelial ovarian cancer progression.Clin Exp Metastasis, 2010, 27(8):557-569.
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32.	Pértega-Gomes N, Vizcaíno JR, Miranda-Gonçalves V, et al.Monocarboxylate transporter 4(MCT4)and CD147 overexpression is associated with poor prognosis in prostate cancer.BMC Cancer, 2011, 11:312.
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34.	Curry JM, Tuluc M, Whitaker-Menezes D, et al.Cancer metabolism, stemness and tumor recurrence:MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer.Cell Cycle, 2013, 12(9):1371-1384.
35.	Sweeny L, Dean NR, Frederick JW, et al.CD147 expression in advanced cutaneous squamous cell carcinoma.J Cutan Pathol, 2012, 39(6):603-609.
36.	De Oliveira AT, Pinheiro C, Longatto-Filho A, et al.Co-expression of monocarboxylate transporter 1(MCT1)and its chaperone(CD147)is associated with low survival in patients with gastrointestinal stromal tumors(GISTs).J Bioenerg Biomembr, 2012, 44(1):171-178.
37.	Kirk P, Wilson MC, Heddle C, et al.CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression.EMBO J, 2000, 19(15):3896-3904.
38.	Wilson MC, Meredith D, Halestrap AP.Fluorescence resonance energy transfer studies on the interaction between the lactate transporter MCT1 and CD147 provide information on the topology and stoichiometry of the complex in situ.J Biol Chem, 2002, 277(5):3666-3672.
39.	Gallagher SM, Castorino JJ, Wang D, et al.Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231.Cancer Res, 2007, 67(9):4182-4189.
40.	Makuc J, Cappellaro C, Boles E.Co-expression of a mammalian accessory trafficking protein enables functional expression of the rat MCT1 monocarboxylate transporter in Saccharomyces cerevisiae.FEMS Yeast Res, 2004, 4(8):795-801.
41.	Philp NJ, Ochrietor JD, Rudoy C, et al.Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin-null mouse.Invest Ophthalmol Vis Sci, 2003, 44(3):1305-1311.
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45.	Le Floch R, Chiche J, Marchiq I, et al.CD147 subunit of lactate/H⁺symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors.Proc Natl Acad Sci U S A, 2011, 108(40):16663-16668.
46.	Schneiderhan W, Scheler M, Holzmann KH, et al.CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models.Gut, 2009, 58(10):1391-1398.
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1. Halestrap AP, Meredith D.The SLC16 gene family-from monocarboxylate transporters(MCTs)to aromatic amino acid transporters and beyond.Pflugers Arch, 2004, 447(5):619-628.
2. Halestrap AP.The SLC16 gene family-structure, role and regulation in health and disease.Mol Aspects Med, 2013, 34(2-3):337-349.
3. Pinheiro C, Longatto-Filho A, Azevedo-Silva J, et al.Role of monocarboxylate transporters in human cancers:state of the art.J Bioenerg Biomembr, 2012, 44(1):127-139.
4. Halestrap AP.The monocarboxylate transporter family-structure and functional characterization.IUBMB Life, 2012, 64(1):1-9.
5. Halestrap AP, Price NT.The proton-linked monocarboxylate transporter(MCT)family:structure, function and regulation.Biochem J, 1999, 343 Pt 2:281-299.
6. Pinheiro C, Sousa B, Albergaria A, et al.GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression.Histol Histopathol, 2011, 26(10):1279-1286.
7. Gatenby RA, Gillies RJ.Why do cancers have high aerobic glycolysis?.Nat Rev Cancer, 2004, 4(11):891-899.
8. Frauwirth KA, Thompson CB.Regulation of T lymphocyte metabolism.J Immunol, 2004, 172(8):4661-4665.
9. Fischer K, Hoffmann P, Voelkl S, et al.Inhibitory effect of tumor cell-derived lactic acid on human T cells.Blood, 2007, 109(9):3812-3819.
10. Végran F, Boidot R, Michiels C, et al.Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis.Cancer Res, 2011, 71(7):2550-2560.
11. Ritzhaupt A, Wood IS, Ellis A, et al.Identification of a monocarboxylate transporter isoform type 1(MCT1)on the luminal membrane of human and pig colon.Biochem Soc Trans, 1998, 26(2):S120.
12. Pinheiro C, Longatto-Filho A, Scapulatempo C, et al.Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas.Virchows Arch, 2008, 452(2):139-146.
13. Koukourakis MI, Giatromanolaki A, Harris AL, et al.Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas:a metabolic survival role for tumor-associated stroma.Cancer Res, 2006, 66(2):632-637.
14. Asada K, Miyamoto K, Fukutomi T, et al.Reduced expression of GNA11 and silencing of MCT1 in human breast cancers.Oncology, 2003, 64(4):380-388.
15. Pinheiro C, Albergaria A, Paredes J, et al.Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma.Histopathology, 2010, 56(7):860-867.
16. Pinheiro C, Reis RM, Ricardo S, et al.Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44.J Biomed Biotechnol, 2010, 2010:427694.
17. Martins D, Beça FF, Sousa B, et al.Loss of caveolin-1 and gain of MCT4 expression in the tumor stroma key events in the progression from an in situ to an invasive breast carcinoma.Cell Cycle, 2013, 12(16):2684-2690.
18. Hussien R, Brooks GA.Mitochondrial and plasma membrane lactate transporter and lactate dehydrogenase isoform expression in breast cancer cell lines.Physiol Genomics, 2011, 43(5):255-264.
19. Froberg MK, Gerhart DZ, Enerson BE, et al.Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues.Neuroreport, 2001, 12(4):761-765.
20. Mathupala SP, Parajuli P, Sloan AE.Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma:an in vitro study.Neurosurgery, 2004, 55(6):1410-1419.
21. 21王晓澍.CD147、MCT1在人脑胶质瘤中的表达及CD147单抗对U251细胞代谢干预的实验研究.四川:四川大学, 2006.
22. Fang J, Quinones QJ, Holman TL, et al.The H⁺-linked monocarboxylate transporter(MCT1/SLC16A1):a potential therapeutic target for high-risk neuroblastoma.Mol Pharmacol, 2006, 70(6):2108-2115.
23. Li KK, Pang JC, Ching AK, et al.miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1.Hum Pathol, 2009, 40(9):1234-1243.
24. Miranda-Gonçalves V, Honavar M, Pinheiro C, et al.Monocarboxylate transporters(MCTs)in gliomas:expression and exploitation as therapeutic targets.Neuro Oncol, 2013, 15(2):172-188.
25. Koukourakis MI, Giatromanolaki A, Bougioukas G, et al.Lung cancer:a comparative study of metabolism related protein expression in cancer cells and tumor associated stroma.Cancer Biol Ther, 2007, 6(9):1476-1479.
26. Ladanyi M, Antonescu CR, Drobnjak M, et al.The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147.Am J Pathol, 2002, 160(4):1215-1221.
27. Pinheiro C, Longatto-Filho A, Simões K, et al.The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer.Eur J Cancer, 2009, 45(13):2418-2424.
28. Pinheiro C, Longatto-Filho A, Pereira SM, et al.Monocarboxylate transporters 1 and 4 are associated with CD147 in cervical carcinoma.Dis Markers, 2009, 26(3):97-103.
29. Pinheiro C, Longatto-Filho A, Ferreira L, et al.Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma.Int J Gynecol Pathol, 2008, 27(4):568-574.
30. Chen H, Wang L, Beretov J, et al.Co-expression of CD147/EMMPRIN with monocarboxylate transporters and multiple drug resistance proteins is associated with epithelial ovarian cancer progression.Clin Exp Metastasis, 2010, 27(8):557-569.
31. Hao J, Chen H, Madigan MC, et al.Co-expression of CD147(EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression.Br J Cancer, 2010, 103(7):1008-1018.
32. Pértega-Gomes N, Vizcaíno JR, Miranda-Gonçalves V, et al.Monocarboxylate transporter 4(MCT4)and CD147 overexpression is associated with poor prognosis in prostate cancer.BMC Cancer, 2011, 11:312.
33. Zhao Z, Wu MS, Zou C, et al.Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway.Cancer Lett, 2014, 342(1):150-158.
34. Curry JM, Tuluc M, Whitaker-Menezes D, et al.Cancer metabolism, stemness and tumor recurrence:MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer.Cell Cycle, 2013, 12(9):1371-1384.
35. Sweeny L, Dean NR, Frederick JW, et al.CD147 expression in advanced cutaneous squamous cell carcinoma.J Cutan Pathol, 2012, 39(6):603-609.
36. De Oliveira AT, Pinheiro C, Longatto-Filho A, et al.Co-expression of monocarboxylate transporter 1(MCT1)and its chaperone(CD147)is associated with low survival in patients with gastrointestinal stromal tumors(GISTs).J Bioenerg Biomembr, 2012, 44(1):171-178.
37. Kirk P, Wilson MC, Heddle C, et al.CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression.EMBO J, 2000, 19(15):3896-3904.
38. Wilson MC, Meredith D, Halestrap AP.Fluorescence resonance energy transfer studies on the interaction between the lactate transporter MCT1 and CD147 provide information on the topology and stoichiometry of the complex in situ.J Biol Chem, 2002, 277(5):3666-3672.
39. Gallagher SM, Castorino JJ, Wang D, et al.Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231.Cancer Res, 2007, 67(9):4182-4189.
40. Makuc J, Cappellaro C, Boles E.Co-expression of a mammalian accessory trafficking protein enables functional expression of the rat MCT1 monocarboxylate transporter in Saccharomyces cerevisiae.FEMS Yeast Res, 2004, 4(8):795-801.
41. Philp NJ, Ochrietor JD, Rudoy C, et al.Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin-null mouse.Invest Ophthalmol Vis Sci, 2003, 44(3):1305-1311.
42. Deora AA, Philp N, Hu J, et al.Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia.Proc Natl Acad Sci U S A, 2005, 102(45):16245-16250.
43. Wilson MC, Meredith D, Fox JE, et al.Basigin(CD147)is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4:the ancillary protein for the insensitive MCT2 is EMBIGIN(gp70).J Biol Chem, 2005, 280(29):27213-27221.
44. Pan Y, He B, Song G, et al.CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells.Oncol Rep, 2012, 27(6):2003-2009.
45. Le Floch R, Chiche J, Marchiq I, et al.CD147 subunit of lactate/H⁺symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors.Proc Natl Acad Sci U S A, 2011, 108(40):16663-16668.
46. Schneiderhan W, Scheler M, Holzmann KH, et al.CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models.Gut, 2009, 58(10):1391-1398.
47. Walters DK, Arendt BK, Jelinek DF.CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells.Cell Cycle, 2013, 12(19):3175-3183.
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