1Department of Gastroenterological Surgery, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Rd, Fuzhou 350005, Fujian Province, China, 2Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, 29 Xinquan Rd, Fuzhou 350001, Fujian Province, China, 3Department of Oncological Surgery, The First Hospital of Putian City, 389 Longdejing, Chengxiang District, Putian 351100, Fujian Province, China, 4Department of Gastrointestinal Medicine, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Rd, Fuzhou 350005, Fujian Province, China, 5Department of Thoracic Surgery, Shanghai, Pulmonary Hospital of Tongji University, 507 Zhengmin Rd., Shanghai 200433 PR China
TABLE OF CONTENTS
Accumulating evidence suggests that the anti-diabetic drug, metformin, exerts anti-proliferative effects in many types of cancers. However, the function and mechanisms of metformin in human colorectal cancer (CRC) remain unknown. Here, we show that metformin induces growth inhibition and apoptosis through activating AMPK-mTOR pathway in human colorectal cancer cells. Notably, metformin treatment significantly up-regulated adenosine A1 receptor (ADORA1) expression in human colorectal cancer cells, while suppression of ADORA1 activity by its specific inhibitor rescued the growth inhibition induced by metformin. Moreover, ADORA1-mediated growth inhibition and apoptosis induced by metformin is AMPK-mTOR pathway dependent in human colorectal cancer cells. Taken together, these results indicate that metformin suppresses human colorectal cancer growth by inducing apoptosis via ADORA1, which provide evidence the anti-neoplastic effects of metformin in the treatment of human colorectal cancer.
1. Hundal HS, Ramlal T, Reyes R. Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. (J) Endocrinology,131(3):1165-1173 (1992).
4. Liu J, Hou M, Yuan T. Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair (J) Oncol Rep, 28(4):1406-1412 (2012).
8. Ishibashi Y, Matsui T, Takeuchi M. Metformin Inhibits Advanced Glycation End ProductsAGEs)-induced Growth and VEGF Expression in MCF-7 Breast Cancer Cells by Suppressing AGEs Receptor Expression via AMP-activated Protein Kinase (J) Horm Metab Res, 45(5):387-390 (2013).
14. Scotland S, Saland E, Skuli N. Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. (J) Leukemia, 27(11):2129-2138 (2013).
15. Fredholm B B, IJzerman A P, Jacobson K A. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. (J) Pharmacol Rev, 53(4):527-552 (2001).
16. Merrill J T, Shen C, Schreibman D. Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. (J) Arthritis Rheum, 40(7):1308-1315 (1997).
17. Salmon J E, Cronstein B N. Fc gamma receptor-mediated functions in neutrophils are modulated by adenosine receptor occupancy. A1 receptors are stimulatory and A2 receptors are inhibitory. (J) J Immunol, 145(7):2235-2240 (1990).
18. Salmon J E, Brogle N, Brownlie C. Human mononuclear phagocytes express adenosine A1 receptors. A novel mechanism for differential regulation of Fc gamma receptor function. (J) J Immunol, 151(5):2775-2785 (1993).
19. Lee H T, Gallos G, Nasr S H. A1 adenosine receptor activation inhibits inflammation, necrosis, and apoptosis after renal ischemia-reperfusion injury in mice. (J) J Am Soc Nephrol, 15(1):102-111 (2004).
20. Lee H T, Xu H, Nasr S H. A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion. (J) Am J Physiol Renal Physiol, 286(2):F298-F306 (2004).
21. Tsutsui S, Schnermann J, Noorbakhsh F. A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. (J). J Neurosci, 24(6):1521-1529 (2004).
22. Liao Y, Takashima S, Asano Y. Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. (J) Circ Res, 93(8):759-766 (2003).
24. Mirza A, Basso A, Black S. RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis. (J) Cancer Biol Ther, 4(12):1355-1360 (2005).
26. Merighi S, Varani K, Gessi S. Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line. (J) Br J Pharmacol, 134(6):1215-1226 (2001).
27. Colquhoun A, Newsholme E A. Inhibition of human tumour cell proliferation by analogues of adenosine. (J) Cell Biochem Funct, 15(2):135-139 (1997).
28. Saito M, Yaguchi T, Yasuda Y. Adenosine suppresses CW2 human colonic cancer growth by inducing apoptosis via A(1) adenosine receptors. (J) Cancer Lett, 290(2):211-215 (2010).
29. Sai K, Yang D, Yamamoto H. A(1) adenosine receptor signal and AMPK involving caspase-9/-3 activation are responsible for adenosine-induced RCR-1 astrocytoma cell death. (J) Neurotoxicology, 27(4):458-467 (2006).
31. Ben S I, Le Marchand-Brustel Y, Tanti J F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug?. (J) Mol Cancer Ther, 9(5):1092-1099 (2010)
34. Dowling R J, Zakikhani M, Fantus I G. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. (J) Cancer Res, 67(22):10804-10812 (2007).
37. Zakikhani M, Dowling R J, Sonenberg N. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. (J) Cancer Prev ResPhila, 1(5):369-375 (2008).
38. Christofi F L, Zhang H, Yu J G. Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system. (J) J Comp Neurol, 439(1):46-64 (2001).
Key Words: Metformin, Colorectal Cancer, Adenosine A1 Receptor, Cell Growth, Apoptosis
Send correspondence to: Bin Lan, Department of Gastroenterological Surgery, the First Affiliated Hospital, Fujian Medical University, 20 Chazhong Rd, Fuzhou 350005, Fujian Province, China, Tel: 8613705006909, Fax: 86059187981028, E-mail: firstname.lastname@example.org.