Blockade of fructose transporter protein GLUT5 inhibits proliferation of colon cancer cells: proof of concept for a new class of anti-tumor therapeutics
Tóm tắt
Despite the fact that colorectal cancer (CRC) is one of the most commonly diagnosed cancers in men and women, its current treatment remains unsatisfactory and therefore novel studies proposing new approaches are necessary. A high sugar diet is believed to promote carcinogenesis. Fructose is absorbed from the gastrointestinal tract by members of the glucose transporter family—GLUT. The aim of the study was to characterize the expression of GLUT5 at mRNA level in CRC patients. Moreover, our goal was to elucidate the molecular role of GLUT5 in CRC and assess whether GLUT5 inhibitor may affect the viability of colon cancer cells. The expression of GLUT5 at mRNA level was characterized based on 30 samples from resected colorectal cancers and 30 healthy colonic mucosa specimens from surgical margins. The inhibitory effect of N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSBNA) was assessed on a colon cancer cell line, HT-29, and normal colon epithelium cells—CCD 841 CoN Cells. GLUT5 expression was found in 96.7% of cancer specimens and only in 53.3% of healthy mucosa fragments. In cancer tissue, real-time PCR analysis showed almost 2, fivefold (p< 0.001) increase of GLUT5 mRNA expression level compared with the healthy intestinal mucosa. GLUT5 inhibitor, MSNBA (10 µM) significantly decreased the viability of colon cancer cells, while barely affected the viability of normal colon epithelium cells. Our study suggests that a strong focus should be put on GLUT5 and its inhibitors for both diagnostic and therapeutic purposes in CRC.
Tài liệu tham khảo
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86. https://doi.org/10.1002/ijc.29210.
Stintzing S. Management of colorectal cancer. F1000Prime Rep. 2014;6:108. https://doi.org/10.12703/P6-108.
Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011. CA Cancer J Clin. 2011;61:212–36. https://doi.org/10.3322/caac.20121.
Kuipers EJ, Grady WM, Lieberman D, Seufferlein T, Sung JJ, Boelens PG, et al. Colorectal cancer. Nat Rev Dis Prim. 2015. https://doi.org/10.1038/nrdp.2015.65.
Colorectal Cancer: Statistics|Cancer. Net https://www.cancer.net/cancer-types/colorectal-cancer/statistics. Accessed 23 Oct 2020
Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5:1–30. https://doi.org/10.1038/s41392-020-0116-z.
Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490–502. https://doi.org/10.1016/S0140-6736(13)61649-9.
Stewart B, Wild CP. World Cancer Report 2014. Lyon: International Agency for Research on Cancer; 2014.
Tasevska N, Jiao L, Cross AJ, Kipnis V, Subar AF, Hollenbeck A, et al. Sugars in diet and risk of cancer in the NIH-AARP Diet and Health Study. Int J Cancer. 2012;130:159–69. https://doi.org/10.1002/ijc.25990.
Van Cutsem E, Nordlinger B, Cervantes A. ESMO Guidelines Working Group. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol. 2010;21:v93–7. https://doi.org/10.1093/annonc/mdq222.
Ristvedt SL, Pruitt SL, Trinkaus KM. Appraisal of emerging symptoms of colorectal cancer: associations with dispositional, demographic, and tumor characteristics. J Behav Med. 2014;37:698–708. https://doi.org/10.1007/s10865-013-9519-4.
Ferrier DR. Lippincott illustrated reviews: Biochemistry. 7th ed. Walters Kluwer: Lippincott; 2020.
Manolescu AR, Witkowska K, Kinnaird A, Cessford T, Cheeseman C. Facilitated hexose transporters: new perspectives on form and function. Physiology (Bethesda). 2007;22:234–40. https://doi.org/10.1152/physiol.00011.2007.
George Thompson AM, Ursu O, Babkin P, Iancu CV, Whang A, Oprea TI, et al. Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation. Sci Rep. 2016;6:1–9. https://doi.org/10.1038/srep24240.
Koepsell H. Glucose transporters in the small intestine in health and disease. Pflugers Arch Eur J Physiol. 2020;472:1207–48. https://doi.org/10.1007/s00424-020-02439-5.
Merigo F, Brandolese A, Facchin S, Missaggia S, Bernardi P, Boschi F, et al. Glucose transporter expression in the human colon. World J Gastroenterol. 2018;24:775–93. https://doi.org/10.3748/wjg.v24.i7.775.
Godoy A, Ulloa V, Rodríguez F, Reinicke K, Yañez AJ, de los García MA, et al. Differential subcellular distribution of glucose transporters GLUT1–6 and GLUT9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues. J Cell Physiol. 2006;207:614–27. https://doi.org/10.1002/jcp.20606.
Douard V, Ferraris RP. The role of fructose transporters in diseases linked to excessive fructose intake. J Physiol. 2013;591:401–14. https://doi.org/10.1113/jphysiol.2011.215731.
Medina Villaamil V, Aparicio Gallego G, Valbuena Rubira L, García Campelo R, Valladares-Ayerbes M, Grande Pulido E, et al. Fructose transporter Glut5 expression in clear renal cell carcinoma. Oncol Rep. 2011;25:315–23. https://doi.org/10.3892/or.2010.1096.
Douard V, Ferraris RP. Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab. 2008;295:227–37. https://doi.org/10.1152/ajpendo.90245.2008.
Nakagawa T, Lanaspa M, Millan IS, Fini M, Rivard C, Sanchez-Lozada L, et al. Fructose contributes to the Warburg effect for cancer growth. Cancer Metab. 2020;8:16. https://doi.org/10.1186/s40170-020-00222-9.
Weng Y, Zhu J, Chen Z, Fu J, Zhang F. Fructose fuels lung adenocarcinoma through GLUT5 comment. Cell Death Dis. 2018. https://doi.org/10.1038/s41419-018-0630-x.
Santhekadur PK. The dark face of fructose as a tumor promoter. Genes Dis. 2020;7:163–5. https://doi.org/10.1016/j.gendis.2019.10.001.
Weng Y, Fan X, Bai Y, Wang S, Huang H, Yang H, et al. SLC2A5 promotes lung adenocarcinoma cell growth and metastasis by enhancing fructose utilization. Cell Death Discov. 2018;4:38. https://doi.org/10.1038/s41420-018-0038-5.
Park G-B, Jeong J-Y, Kim D. GLUT5 regulation by AKT1/3-miR-125b-5p downregulation induces migratory activity and drug resistance in TLR-modified colorectal cancer cells. Carcinogenesis. 2020;41:1329–40. https://doi.org/10.1093/carcin/bgaa074.
Charrez B, Qiao L, Hebbard L. The role of fructose in metabolism and cancer. Horm Mol Biol Clin Investig. 2015;22:79–89. https://doi.org/10.1515/hmbci-2015-0009.
Goncalves MD, Lu C, Tutnauer J, Hartman TE, Hwang SK, Murphy CJ, et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science. 2019;363:1345–9. https://doi.org/10.1126/science.aat8515.
Zwarts I, van Zutphen T, Kruit JK, Liu W, Oosterveer MH, Verkade HJ, et al. Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR. Sci Rep. 2019;9:1–10. https://doi.org/10.1038/s41598-019-45803-x.
Thomik T, Wittig I, Choe JY, Boles E, Oreb M. An artificial transport metabolon facilitates improved substrate utilization in yeast. Nat Chem Biol. 2017;13:1158–63. https://doi.org/10.1038/nchembio.2457.
Port AM, Ruth MR, Istfan NW. Fructose consumption and cancer. Curr Opin Endocrinol Diabetes Obes. 2012;19:367–74. https://doi.org/10.1097/MED.0b013e328357f0cb.
Fan X, Liu H, Liu M, Wang Y, Qiu L, Cui Y. Increased utilization of fructose has a positive effect on the development of breast cancer. PeerJ. 2017. https://doi.org/10.7717/peerj.3804.
Liu H, Huang D, McArthur DL, Boros LG, Nissen N, Heaney AP. Fructose induces transketolase flux to promote pancreatic cancer growth. Cancer Res. 2010;70:6368–76. https://doi.org/10.1158/0008-5472.CAN-09-4615.