| 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. | |
| | |
MedLine Citation:
|
PMID: 20228137 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Carolyn Algire; Lilian Amrein; Mahvash Zakikhani; Lawrence Panasci; Michael Pollak |
Related Documents
:
|
11956637 - Inhibition by long-term fermented miso of induction of gastric tumors by n-methyl-n'-ni... 9044827 - Suppression of preneoplastic changes in the intestine of rats fed low levels of polyami... 11341047 - A protective role of dietary vitamin d3 in rat colon carcinogenesis. 8887887 - Lack of inhibitory effect of benzyl isothiocyanate on 2-amino-1-methyl-6-phenylimidazo ... 12840197 - Fat and protein from olive oil-fried sardines interact to normalize serum lipoproteins ... 12822707 - High salt intake appears to increase bone resorption in postmenopausal women but high p... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-01 |
Journal Detail:
|
Title: Endocrine-related cancer Volume: 17 ISSN: 1479-6821 ISO Abbreviation: Endocr. Relat. Cancer Publication Date: 2010 Jun |
Date Detail:
|
Created Date: 2010-03-15 Completed Date: 2010-06-24 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 9436481 Medline TA: Endocr Relat Cancer Country: England |
Other Details:
|
Languages: eng Pagination: 351-60 Citation Subset: IM |
Affiliation:
|
Department of Experimental Medicine, McGill University, Montr?al, Qu?bec, Canada. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
AMP-Activated Protein Kinases
/
metabolism Acetyl-CoA Carboxylase / metabolism Animals Apoptosis / drug effects Carcinoma / drug therapy*, enzymology Colonic Neoplasms / drug therapy*, enzymology Energy Intake / drug effects* Fatty Acid Synthetase Complex / antagonists & inhibitors*, biosynthesis Hypoglycemic Agents / therapeutic use* Insulin / blood Male Membrane Proteins / metabolism Metformin / therapeutic use* Mice Mice, Inbred C57BL Mitochondrial Proteins / metabolism Protein-Serine-Threonine Kinases / metabolism Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
|
//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
|
0/BNip3 protein, mouse; 0/Hypoglycemic Agents; 0/Membrane Proteins; 0/Mitochondrial Proteins; 11061-68-0/Insulin; 657-24-9/Metformin; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 6.-/Fatty Acid Synthetase Complex; EC 6.4.1.2/Acetyl-CoA Carboxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Histology-specific risks in testicular cancer in immigrants to Sweden.
Next Document: The power of charisma--perceived charisma inhibits the frontal executive network of believers in int...