Abstract
MicroRNAs play an important role in tumor development and progression. Tumor growth is closely associated with glucose metabolism. Specifically, tumor cells produce energy (ATP) under aerobic and anaerobic conditions through glycolysis and metabolites, such as lactic acid and ATP, as a result of the Warburg effect. However, the transport of glucose into cells depends on protein transporters in the cell membrane. Therefore, this area has recently become a topic of interest for research on targeted cancer therapy. We found that miRNA-451 inhibits the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway to modify the biological behavior of glioma cells. Inhibiting the PI3K/Akt pathway may prevent glucose-addicted cancer cells from performing glycolysis. Akt directly affects glycolysis by regulating the localization of the glucose transporter 1 (GLUT1). However, how miRNA-451 regulates glucose transporters on the cell membrane and affects the regulatory mechanisms of glucose metabolism in glioma cells remains unclear. Consequently, we predict and verify related gene protein interactions. By targeting CAB 39, miRNA-451 likely triggers the LKB1/AMPK/PI3K/AKT pathway, which regulates GLUT1, to inhibit the glucose metabolism of, reduce the energy supply to, and inhibit the proliferation and invasion of glioma cells. Our results suggest a new direction for the treatment of glioma.
Similar content being viewed by others
References
Godlewski J, Nowicki MO, Bronisz A, Nuovo G, Palatini J, De Lay M, Van Brocklyn J, Ostrowski MC, Chiocca EA, Lawler SE. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol Cell. 2010;37:620–32. doi:10.1016/j.molcel.2010.02.018.
Samaras V, Piperi C, Korkolopoulou P, Zisakis A, Levidou G, Themistocleous MS, Boviatsis EI, Sakas DE, Lea RW, Kalofoutis A, Patsouris E. Application of the ELISPOT method for comparative analysis of interleukin (IL)-6 and IL-10 secretion in peripheral blood of patients with astroglial tumors. Mol Cell Biochem. 2007;304:343–51. doi:10.1007/s11010-007-9517-3.
Tu Y, Gao X, Li G, Fu H, Cui D, Liu H, Jin W, Zhang Y. MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res. 2013;73:6046–55. doi:10.1158/0008-5472.CAN-13-0358.
Theeler BJ, Groves MD. High-grade gliomas. Curr Treat Options Neurol. 2011;13:386–99. doi:10.1007/s11940-011-0130-0.
Rolle CE, Sengupta S, Lesniak MS. Challenges in clinical design of immunotherapy trials for malignant glioma. Neurosurg Clin N Am. 2010;21:201–14. doi:10.1016/j.nec.2009.08.002.
Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8:774–85. doi:10.1038/nrm2249.
Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654–62. doi:10.1002/jcp.20166.
Warburg O. On the origin of cancer cells. Science. 1956;123:309–14. doi:10.1126/science.123.3191.309.
Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66:8927–30. doi:10.1158/0008-5472.CAN-06-1501.
Duelli R, Kuschinsky W. Brain glucose transporters: relationship to local energy demand. News Physiol Sci. 2001;16:71–6.
Yeh WL, Lin CJ, Fu WM. Enhancement of glucose transporter expression of brain endothelial cells by vascular endothelial growth factor derived from glioma exposed to hypoxia. Mol Pharmacol. 2008;73:170–7. doi:10.1124/mol.107.038851.
Bell GI, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, Fukumoto H, Seino S. Molecular biology of mammalian glucose transporters. Diabetes Care. 1990;13:198–208. doi:10.2337/diacare.13.3.198.
Tennant DA, Durán RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10:267–77. doi:10.1038/nrc2817.
Leybaert L. Neurobarrier coupling in the brain: a partner of neurovascular and neurometabolic coupling? J Cereb Blood Flow Metab. 2005;25:2–16. doi:10.1038/sj.jcbfm.9600001.
Yamamoto T, Seino Y, Fukumoto H, Koh G, Yano H, Inagaki N, Yamada Y, Inoue K, Manabe T, Imura H. Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun. 1990;170:223–30. doi:10.1016/0006-291X(90)91263-R.
Grover-McKay M, Walsh SA, Seftor EA, Thomas PA, Hendrix MJ. Role for glucose transporter 1 protein in human breast cancer. Pathol Oncol Res. 1998;4:115–20. doi:10.1007/BF02904704.
Leybaert L, De Bock M, Van Moorhem M, Decrock E, De Vuyst E. Neurobarrier coupling in the brain: adjusting glucose entry with demand. J Neurosci Res. 2007;85:3213–20. doi:10.1002/jnr.21189.
Demasi AP, Costa AF, Altemani A, Furuse C, Araújo NS, Araújo VC. Glucose transporter protein 1 expression in mucoepidermoid carcinoma of salivary gland: correlation with grade of malignancy. Int J Exp Pathol. 2010;91:107–13. doi:10.1111/j.1365-2613.2009.00702.x.
Kloosterman WP, Plasterk RH. The diverse functions of microRNAs in animal development and disease. Dev Cell. 2006;11:441–50. doi:10.1016/j.devcel.2006.09.009.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33. doi:10.1016/j.cell.2009.01.002.
Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69. doi:10.1038/nrc1840.
Lawler S, Chiocca EA. Emerging functions of microRNAs in glioblastoma. J Neuro-Oncol. 2009;92:297–306. doi:10.1007/s11060-009-9843-2.
Varis A, Wolf M, Monni O, Vakkari ML, Kokkola A, Moskaluk C, Frierson H, Powell SM, Knuutila S, Kallioniemi A, El-Rifai W. Targets of gene amplification and overexpression at 17q in gastric cancer. Cancer Res. 2002;62:2625–9.
Mahlamäki EH, Bärlund M, Tanner M, Gorunova L, Höglund M, Karhu R, Kallioniemi A. Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer. Genes Chromosom Cancer. 2002;35:353–8. doi:10.1002/gcc.10122.
Tian Y, Nan Y, Han L, Zhang A, Wang G, Jia Z, Hao J, Pu P, Zhong Y, Kang C. MicroRNA miR-451 downregulates the PI3K/AKT pathway through CAB39 in human glioma. Int J Oncol. 2012;40:1105–12. doi:10.3892/ijo.2011.1306.
Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251–62. doi:10.1038/nrm3311.
Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9:563–75. doi:10.1038/nrc2676.
Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011;25:1895–908. doi:10.1101/gad.17420111.
Schiewer MJ, Knudsen KE. AMPed up to treat prostate cancer: novel AMPK activators emerge for cancer therapy. EMBO Mol Med. 2014;6:439–41. doi:10.1002/emmm.201303737.
Liang J, Mills GB. AMPK: a contextual oncogene or tumor suppressor? Cancer Res. 2013;73:2929–35. doi:10.1158/0008-5472.CAN-12-3876.
Goyal A, Neill T, Owens RT, Schaefer L, Iozzo RV. Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells. Matrix Biol. 2014;34:46–54. doi:10.1016/j.matbio.2013.12.011.
Cheng CK, Fan QW, Weiss WA. PI3K signaling in glioma—animal models and therapeutic challenges. Brain Pathol. 2009;19:112–20. doi:10.1111/j.1750-3639.2008.00233.x.
Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem. 2001;70:535–602. doi:10.1146/annurev.biochem.70.1.535.
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74. doi:10.1016/j.cell.2007.06.009.
Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64:3892–9. doi:10.1158/0008-5472.CAN-03-2904.
Kim Y. Regulation of cell proliferation and migration in glioblastoma: new therapeutic approach. Front Oncol. 2013;3:53.
Carling D, Mayer FV, Sanders MJ, Gamblin SJ. Amp-activated protein kinase: Nature’s energy sensor. Nat Chem Biol. 2011;7:512–8.
Basu S, Hubbard B, Shevach EM. Foxp3-mediated inhibition of akt inhibits glut1 (glucose transporter 1) expression in human t regulatory cells. J Leukoc Biol. 2015;97:279–83.
Gwak H, Haegeman G, Tsang BK, Song YS. Cancer-specific interruption of glucose metabolism by resveratrol is mediated through inhibition of akt/glut1 axis in ovarian cancer cells. Mol Carcinog. 2015;54:1529–40.
Ameres SL, Zamore PD. Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol. 2013;14:475–88. doi:10.1038/nrm3611.
Nie S, Li K, Huang Y, Hu Q, Gao X, Jie S. miR-495 mediates metabolic shift in glioma cells via targeting Glut1. J Craniomaxillofac Surg. 2015;26:e155–8. doi:10.1097/SCS.0000000000001385.
Sone H, Deo BK, Kumagai AK. Enhancement of glucose transport by vascular endothelial growth factor in retinal endothelial cells. Invest Ophthalmol Vis Sci. 2000;41:1876–84.
Fan J, Yang Y, Xie JY, Ly YL, Shi K, Huang YQ. MicroRNA-144 mediates metabolic shift in ovarian cancer cells by directly targeting glut. Tumour Biol. 2015. doi:10.1007/s13277-015-4558-9.
Yamasaki T, Seki N, Yoshino H, Itesako T, Yamada Y, Tatarano S, Hidaka H, Yonezawa T, Nakagawa M, Enokida H. Tumor-suppressive microRNA-1291 directly regulates glucose transporter 1 in renal cell carcinoma. Cancer Sci. 2013;104:1411–9. doi:10.1111/cas.12240.
Yang X, Cheng Y, Li P, Tao J, Deng X, Zhang X, Gu M, Lu Q, Yin C. A lentiviral sponge for miRNA-21 diminishes aerobic glycolysis in bladder cancer T24 cells via the PTEN/PI3K/AKT/mTOR axis. Tumor Biol. 2015;36:383–91. doi:10.1007/s13277-014-2617-2.
Acknowledgments
This work was supported by the China National Natural Scientific Fund (81572490) and the Tianjin Science and Technology Committee (13JCQNJC10800, 13JCZDJC31000).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None
Additional information
Hongbao Guo, Yang Nan, and Yingwei Zhen contributed equally to this work.
Rights and permissions
About this article
Cite this article
Guo, H., Nan, Y., Zhen, Y. et al. miRNA-451 inhibits glioma cell proliferation and invasion by downregulating glucose transporter 1. Tumor Biol. 37, 13751–13761 (2016). https://doi.org/10.1007/s13277-016-5219-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-016-5219-3