Metformin suppresses CRC growth by inducing apoptosis via ADORA1.

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]  G. Maity,et al.  Abstract 3572: Metformin inhibits the oncogenic potential and invasiveness of pancreatic cancer cells targeting CCN1-CXCR4 axis : A new perspective for an old antidiabetic drug , 2015 .

[2]  I. Ben-Sahra,et al.  Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia. , 2014, Cancer letters.

[3]  C. Junot,et al.  Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells , 2013, Leukemia.

[4]  S. Yamagishi,et al.  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 , 2012, Hormone and Metabolic Research.

[5]  Shuxu Zhang,et al.  Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair. , 2012, Oncology reports.

[6]  T. Kourelis,et al.  Metformin and cancer: new applications for an old drug , 2012, Medical Oncology.

[7]  G. Z. Rocha,et al.  Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth , 2011, Clinical Cancer Research.

[8]  P. Goodwin,et al.  Understanding the benefit of metformin use in cancer treatment , 2011, BMC medicine.

[9]  R. Memmott,et al.  Metformin Prevents Tobacco Carcinogen–Induced Lung Tumorigenesis , 2010, Cancer Prevention Research.

[10]  B. Viollet,et al.  Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. , 2010, Cell metabolism.

[11]  I. Ben-Sahra,et al.  Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug? , 2010, Molecular Cancer Therapeutics.

[12]  T. Nakano,et al.  Adenosine suppresses CW2 human colonic cancer growth by inducing apoptosis via A(1) adenosine receptors. , 2010, Cancer letters.

[13]  Funda Meric-Bernstam,et al.  Metformin: A Therapeutic Opportunity in Breast Cancer , 2010, Clinical Cancer Research.

[14]  Bolin Liu,et al.  Metformin induces unique biological and molecular responses in triple negative breast cancer cells , 2009, Cell cycle.

[15]  R. Hill,et al.  PTEN, Stem Cells, and Cancer Stem Cells* , 2009, Journal of Biological Chemistry.

[16]  A. Thor,et al.  Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro , 2009, Cell cycle.

[17]  R. McLendon,et al.  Brain Cancer Stem Cells Display Preferential Sensitivity to Akt Inhibition , 2008, Stem cells.

[18]  Nahum Sonenberg,et al.  The Effects of Adiponectin and Metformin on Prostate and Colon Neoplasia Involve Activation of AMP-Activated Protein Kinase , 2008, Cancer Prevention Research.

[19]  N. Sonenberg,et al.  Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. , 2007, Cancer research.

[20]  Nahum Sonenberg,et al.  Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. , 2006, Cancer research.

[21]  Hideyuki Yamamoto,et al.  A(1) adenosine receptor signal and AMPK involving caspase-9/-3 activation are responsible for adenosine-induced RCR-1 astrocytoma cell death. , 2006, Neurotoxicology.

[22]  J. Lachowicz,et al.  RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis , 2005, Cancer biology & therapy.

[23]  Dario R Alessi,et al.  Metformin and reduced risk of cancer in diabetic patients , 2005, BMJ : British Medical Journal.

[24]  M. Hori,et al.  Activation of Adenosine A1 Receptor Attenuates Cardiac Hypertrophy and Prevents Heart Failure in Murine Left Ventricular Pressure-Overload Model , 2003, Circulation research.

[25]  B. Fredholm,et al.  International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. , 2001, Pharmacological reviews.

[26]  K. Varani,et al.  Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line , 2001, British journal of pharmacology.

[27]  L. Witters.  The blooming of the French lilac. , 2001, The Journal of clinical investigation.

[28]  Jianjing Xue,et al.  Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system , 2001, The Journal of comparative neurology.

[29]  D. Ferrari,et al.  Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells , 2001, British journal of pharmacology.

[30]  B. Cronstein,et al.  Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes. A mechanism for methotrexate‐induced nodulosis in rheumatoid arthritis , 1997 .

[31]  E. Newsholme,et al.  Inhibition of human tumour cell proliferation by analogues of adenosine , 1997, Cell biochemistry and function.

[32]  C. Ho,et al.  Differential expression of adenosine A1 receptors in colorectal cancer and related mucosa. , 1996, Cancer letters.

[33]  R. Kimberly,et al.  Human mononuclear phagocytes express adenosine A1 receptors. A novel mechanism for differential regulation of Fc gamma receptor function. , 1993, Journal of immunology.

[34]  Lawrence A Leiter,et al.  Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. , 1992, Endocrinology.

[35]  B. Cronstein,et al.  Fc gamma receptor-mediated functions in neutrophils are modulated by adenosine receptor occupancy. A1 receptors are stimulatory and A2 receptors are inhibitory. , 1990, Journal of immunology.

[36]  芦沼 宏典.  Antiproliferative action of metformin in human lung cancer cell lines , 2012 .

[37]  S. Nasr,et al.  A 1 Adenosine Receptor Activation Inhibits Inflammation , Necrosis , and Apoptosis after Renal Ischemia-Reperfusion Injury in Mice , 2003 .