Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase

被引:199
作者
Algire, Carolyn [2 ]
Amrein, Lilian [3 ]
Zakikhani, Mahvash [3 ]
Panasci, Lawrence [1 ]
Pollak, Michael [1 ]
机构
[1] McGill Univ, Jewish Gen Hosp, Dept Oncol, Montreal, PQ H3T 1E2, Canada
[2] McGill Univ, Dept Expt Med, Montreal, PQ H3A 1A3, Canada
[3] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
关键词
BREAST-CANCER CELLS; ACTIVATED PROTEIN-KINASE; FACTOR BINDING PROTEIN-1; BODY-MASS INDEX; COLORECTAL-CANCER; C-PEPTIDE; INSULIN; OBESITY; RISK; MORTALITY;
D O I
10.1677/ERC-09-0252
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The molecular mechanisms responsible for the association of obesity with adverse colon cancer outcomes are poorly understood. We investigated the effects of a high-energy diet on growth of an in vivo colon cancer model. Seventeen days following the injection of 5X10(5) MC38 colon carcinoma cells, tumors from mice on the high-energy diet were approximately twice the volume of those of mice on the control diet. These findings were correlated with the observation that the high-energy diet led to elevated insulin levels, phosphorylated AKT, and increased expression of fatty acid synthase (FASN) by the tumor cells. Metformin, an antidiabetic drug, leads to the activation of AMPK and is currently under investigation for its antineoplastic activity. We observed that metformin blocked the effect of the high-energy diet on tumor growth, reduced insulin levels, and attenuated the effect of diet on phosphorylation of AKT and expression of FASN. Furthermore, the administration of metformin led to the activation of AMPK, the inhibitory phosphorylation of acetyl-CoA carboxylase, the upregulation of BNIP3 and increased apoptosis as estimated by poly (ADP-ribose) polymerase (PARP) cleavage. Prior work showed that activating mutations of PI3K are associated with increased AKT activation and adverse outcome in colon cancer; our results demonstrate that the aggressive tumor behavior associated with a high-energy diet has similar effects on this signaling pathway. Furthermore, metformin is demonstrated to reverse the effects of the high-energy diet, thus suggesting a potential role for this agent in the management of a metabolically defined subset of colon cancers. Endocrine-Related Cancer (2010) 17 351-360
引用
收藏
页码:351 / 360
页数:10
相关论文
共 37 条
[1]   Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells [J].
Bandyopadhyay, S ;
Zhan, R ;
Wang, Y ;
Pai, SK ;
Hirota, S ;
Hosobe, S ;
Takano, Y ;
Saito, K ;
Furuta, E ;
Iiizumi, M ;
Mohinta, S ;
Watabe, M ;
Chalfant, C ;
Watabe, K .
CANCER RESEARCH, 2006, 66 (11) :5934-5940
[2]  
Becker Susen, 2009, Archives of Physiology and Biochemistry, V115, P86, DOI 10.1080/13813450902878054
[3]   Increased cancer-related mortality for patients with type 2 diabetes who use sulforrylureas or insulin [J].
Bowker, SL ;
Majumdar, SR ;
Veugelers, P ;
Johnson, JA .
DIABETES CARE, 2006, 29 (02) :254-258
[4]   Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth [J].
Buzzai, Monica ;
Jones, Russell G. ;
Amaravadi, Ravi K. ;
Lum, Julian J. ;
DeBerardinis, Ralph J. ;
Zhao, Fangping ;
Viollet, Benoit ;
Thompson, Craig B. .
CANCER RESEARCH, 2007, 67 (14) :6745-6752
[5]   OBESITY AND INSULIN LEVELS [J].
CAHILL, GF .
NEW ENGLAND JOURNAL OF MEDICINE, 1971, 284 (22) :1268-&
[6]   Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults [J].
Calle, EE ;
Rodriguez, C ;
Walker-Thurmond, K ;
Thun, MJ .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (17) :1625-1638
[7]   Leptin Signaling in Breast Cancer: An Overview [J].
Cirillo, Donatella ;
Rachiglio, Anna Maria ;
la Montagna, Raffaele ;
Giordano, Antonio ;
Normanno, Nicola .
JOURNAL OF CELLULAR BIOCHEMISTRY, 2008, 105 (04) :956-964
[8]   Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer [J].
Dignam, James J. ;
Polite, Blase N. ;
Yothers, Greg ;
Raich, Peter ;
Colangelo, Linda ;
O'Connell, Michael J. ;
Wolmark, Norman .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2006, 98 (22) :1647-1654
[9]   Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells [J].
Dowling, Ryan J. O. ;
Zakikhani, Mahvash ;
Fantus, I. George ;
Pollak, Michael ;
Sonenberg, Nahum .
CANCER RESEARCH, 2007, 67 (22) :10804-10812
[10]   Metformin and reduced risk of cancer in diabetic patients [J].
Evans, JMM ;
Donnelly, LA ;
Emslie-Smith, AM ;
Alessi, DR ;
Morris, AD .
BMJ-BRITISH MEDICAL JOURNAL, 2005, 330 (7503) :1304-1305