Metformin Inhibits Advanced Glycation End Products (AGEs)-induced Growth and VEGF Expression in MCF-7 Breast Cancer Cells by Suppressing AGEs Receptor Expression via AMP-activated Protein Kinase

Abstract

Metformin use has been reported to decrease breast cancer incidence and mortality in diabetic patients. We have previously shown that advanced glycation end products (AGEs) and their receptor (RAGE) interaction stimulate growth and/or migration of pancreatic cancer and melanoma cells. However, effects of metformin on AGEs-RAGE axis in breast cancers remain unknown. We examined here whether and how metformin could block the AGEs-induced growth and vascular endothelial growth factor (VEGF) expression in MCF-7 breast cancer cells. Cell proliferation was measured with an electron coupling reagent WST-1 based colorimetric assay. Gene expression level was evaluated by real-time reverse-transcription polymerase chain reactions. AGEs significantly increased cell proliferation of MCF-7 cells, which was completely prevented by the treatment with 0.01 or 0.1 mM metformin or anti-RAGE antibodies. Furthermore, metformin at 0.01 mM completely suppressed the AGEs-induced upregulation of RAGE and VEGF mRNA levels in MCF-7 cells. An inhibitor of AMP-activated protein kinase, compound C significantly blocked the growth-inhibitory and RAGE and VEGF suppressing effects of metformin in AGEs-exposed MCF-7 cells. Our present study suggests that metformin could inhibit the AGEs-induced growth and VEGF expression in MCF-7 breast cancer cells by suppressing RAGE gene expression via AMP-activated protein kinase pathway. Metformin may protect against breast cancer expansion in diabetic patients by blocking the AGEs-RAGE axis.

• References

• 1 Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes Care 2010; 33: 1674-1685
• 2 Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Endocr Relat Cancer 2009; 16: 1103-1123
• 3 Larsson SC, Mantzoros CS, Wolk A. Int J Cancer 2007; 121: 856-862
• 4 Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Am J Epidemiol 2004; 159: 1160-1167
• 5 Dowling RJ, Goodwin PJ, Stambolic V. BMC Med 2011; 9: 33
• 6 Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Diabetes Care 2010; 33: 1304-1308
• 7 Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT. Breast Cancer Res Treat 2012; 135: 639-646
• 8 Currie CJ, Poole CD, Jenkins-Jones S, Gale EA, Johnson JA, Morgan CL. Diabetes Care 2012; 35: 299-304
• 9 Yamagishi S, Imaizumi T. Curr Pharm Des 2005; 11: 2279-2299
• 10 Takeuchi M, Kikuchi S, Sasaki N, Suzuki T, Watai T, Iwaki M, Bucala R, Yamagishi S. Curr Alzheimer Res 2004; 1: 39-46
• 11 Abe R, Yamagishi S. Curr Pharm Des 2008; 14: 940-945
• 12 Abe R, Shimizu T, Sugawara H, Watanabe H, Nakamura H, Choei H, Sasaki N, Yamagishi S, Takeuchi M, Shimizu H. J Invest Dermatol 2004; 122: 461-467
• 13 Yamamoto Y, Yamagishi S, Hsu CC, Yamamoto H. Biochem Biophys Res Commun 1996; 222: 700-705
• 14 Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Horm Metab Res. 2012
• 15 Fukami K, Ueda S, Yamagishi S, Kato S, Inagaki Y, Takeuchi M, Motomiya Y, Bucala R, Iida S, Tamaki K, Imaizumi T, Cooper ME, Okuda S. Kidney Int 2004; 66: 2137-2147
• 16 Takino J, Yamagishi S, Takeuchi M. World J Gastroenterol 2012; 18: 1781-1788
• 17 Yamagishi S, Abe R, Inagaki Y, Nakamura K, Sugawara H, Inokuma D, Nakamura H, Shimizu T, Takeuchi M, Yoshimura A, Bucala R, Shimizu H, Imaizumi T. Am J Pathol 2004; 165: 1865-1874
• 18 Schneider BP, Sledge Jr GW. Nat Clin Pract Oncol 2007; 4: 181-189
• 19 Marathe PH, Wen Y, Norton J, Greene DS, Barbhaiya RH, Wilding IR. Br J Clin Pharmacol 2000; 50: 325-332
• 20 Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF, Holme I, Njølstad I, Fletcher A, Nilsson P, Lewington S, Collins R, Gudnason V, Thompson SG, Sattar N, Selvin E, Hu FB, Danesh J. N Engl JMed 2011; 364: 829-841