The Effects of Adiponectin and Metformin on Prostate and Colon Neoplasia Involve Activation of AMP-Activated Protein Kinase

Population studies provide evidence that obesity and insulin resistance are associated not only with elevated serum insulin levels and reduced serum adiponectin levels but also with increased risk of aggressive prostate and colon cancer. We show here that adiponectin activates AMP-activated protein kinase (AMPK) in colon (HT-29) and prostate (PC-3) cancer cells. These results are consistent with prior observations in myocytes, but we show that in epithelial cancer cells AMPK activation is associated with reduction in mammalian target of rapamycin activation as estimated by Ser2448 phosphorylation, with reduction in p70S6 kinase activation as estimated by Thr389 phosphorylation, with ribosomal protein S6 activation as estimated by Ser235/236 phosphorylation, with reduction in protein translation as estimated by [35S]methionine incorporation, and with growth inhibition. Adiponectin-induced growth inhibition is significantly attenuated when AMPK level is reduced using small interfering RNA, indicating that AMPK is involved in mediating the antiproliferative action of this adipokine. Thus, adiponectin has the characteristics of a AMPK-dependent growth inhibitor that is deficient in obesity, and this may contribute to the adverse effects of obesity on neoplastic disease. Furthermore, metformin was observed to activate AMPK and to have growth inhibitory actions on prostate and colon cancer cells, suggesting that this compound may be of particular value in attenuating the adverse effects of obesity on neoplasia.

[1]  D. Bolster,et al.  AMP-activated Protein Kinase Suppresses Protein Synthesis in Rat Skeletal Muscle through Down-regulated Mammalian Target of Rapamycin (mTOR) Signaling* , 2002, The Journal of Biological Chemistry.

[2]  R. DePinho,et al.  The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin , 2005, Science.

[3]  L. Kifle,et al.  Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. , 2006, Cell metabolism.

[4]  I. Ben-Sahra,et al.  The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level , 2008, Oncogene.

[5]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[6]  N. Sonenberg,et al.  mTOR, translation initiation and cancer , 2006, Oncogene.

[7]  Steven B Heymsfield,et al.  Metabolic syndrome in normal-weight Americans: new definition of the metabolically obese, normal-weight individual. , 2004, Diabetes care.

[8]  B. Spiegelman,et al.  Adipogenesis and Obesity: Rounding Out the Big Picture , 1996, Cell.

[9]  G. Bray.  The underlying basis for obesity: relationship to cancer. , 2002, The Journal of nutrition.

[10]  B. Viollet,et al.  Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. , 2007, Cancer research.

[11]  The effects of metformin on pathologic complete response (pCR) rates in diabetic breast cancer (BC) patients receiving neoadjuvant systemic therapy (NST) , 2008 .

[12]  H. Lodish,et al.  Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Majumdar,et al.  Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin , 2006, Diabetes Care.

[14]  A. Prescott,et al.  AMP-activated protein kinase : greater AMP dependence , and preferential nuclear localization , of complexes containing the α 2 isoform , 1998 .

[15]  A. Prescott,et al.  AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. , 1998, The Biochemical journal.

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

[17]  Lewis C Cantley,et al.  The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Osborne,et al.  Hormone responsive human breast cancer in long-term tissue culture: effect of insulin. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Chad M. Trent,et al.  Do low levels of circulating adiponectin represent a biomarker or just another risk factor for the metabolic syndrome? , 2007, Diabetes, obesity & metabolism.

[20]  A. Belfiore.  The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. , 2007, Current pharmaceutical design.

[21]  Michael J Thun,et al.  Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. , 2003, The New England journal of medicine.

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

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

[24]  C. Mantzoros,et al.  Serum Adiponectin Concentrations and Tissue Expression of Adiponectin Receptors Are Reduced in Patients with Prostate Cancer: A Case Control Study , 2007, Cancer Epidemiology Biomarkers & Prevention.

[25]  R. Henry,et al.  Adiponectin: more than just another fat cell hormone? , 2003, Diabetes care.

[26]  Masato Kasuga,et al.  [Obesity and insulin resistance]. , 2009, Nihon rinsho. Japanese journal of clinical medicine.

[27]  L. Klotz,et al.  Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts. , 2007, Journal of the National Cancer Institute.

[28]  D. Hardie.  Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/en.2003-0982 Minireview: The AMP-Activated Protein Kinase Cascade: The Key Sensor of Cellular Energy Status , 2022 .

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

[30]  C. Mantzoros,et al.  Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway. , 2007, Endocrine-related cancer.

[31]  D. Hardie.  AMPK and SNF1: Snuffing Out Stress , 2007, Cell metabolism.

[32]  D. Hardie,et al.  AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. , 2005, Cell metabolism.