Document Detail

Folic acid and its metabolites modulate IGF-I receptor gene expression in colon cancer cells in a p53-dependent manner.
MedLine Citation:
PMID:  16728583     Owner:  NLM     Status:  MEDLINE    
The insulin-like growth factor-I receptor (IGF-IR) has an important role in colorectal cancer development and progression. IGF-IR displays a potent anti-apoptotic activity and is overexpressed in primary tumors and colon cancer-derived cell lines. Folic acid, a member of the vitamin B family, is a chemopreventive agent whose deficiency has been linked to an enhanced colon cancer risk. The present study was aimed at testing the hypothesis that part of the modulatory effect of folic acid on malignant transformation may be attributed to its ability to regulate IGF-IR gene expression. Regulation of IGF-IR gene expression by folic acid was assessed using western blots, RT-PCR, transient transfections and chromatin immunoprecipitation assays. Activation of the IGF-IR signaling pathway was evaluated by measuring phosphorylation of ERK, and apoptosis was assayed using poly (ADP-ribose) polymerase cleavage and annexin V-FITC staining. Results obtained showed that folic acid induced a dose-dependent decrease in IGF-IR protein and mRNA levels in the HCT116 +/+ colon cancer cell line. This effect was associated with a significant reduction in IGF-IR promoter activity. Similar effects were elicited by the folic acid metabolites dihydrofolic acid and tetrahydrofolic acid. In addition, folic acid abrogated the IGF-I-stimulated phosphorylation of the downstream signaling molecule ERK1/2 and exhibited a pro-apoptotic activity. Moreover, folic acid induced a significant decrease in Sp1 binding to the IGF-IR promoter region. Finally, folic acid had no effect in wild-type p53-depleted HCT116 -/- and Caco-2 cells. In conclusion, the mechanism of action of folic acid involves regulation of IGF-IR gene expression. The ability of folic acid to downregulate the IGF-I signal transduction pathway may allow the micronutrient to function as a chemopreventive agent. Folic acid deficiency, on the other hand, may lead to increased IGF-IR gene expression, with ensuing pathological activation by endocrine and/or autocrine/paracrine IGF-I.
Z Attias; H Werner; N Vaisman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Endocrine-related cancer     Volume:  13     ISSN:  1351-0088     ISO Abbreviation:  Endocr. Relat. Cancer     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-05-26     Completed Date:  2006-08-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9436481     Medline TA:  Endocr Relat Cancer     Country:  England    
Other Details:
Languages:  eng     Pagination:  571-81     Citation Subset:  IM    
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
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MeSH Terms
Apoptosis / genetics
Colonic Neoplasms / genetics*
Folic Acid / analogs & derivatives,  metabolism*,  pharmacology*
Gene Expression / drug effects
Gene Expression Regulation, Neoplastic
Promoter Regions, Genetic / drug effects
Receptor, IGF Type 1 / genetics*,  metabolism
Tetrahydrofolates / pharmacology
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics,  physiology*
Reg. No./Substance:
0/Tetrahydrofolates; 0/Tumor Suppressor Protein p53; 29347-89-5/5,6,7,8-tetrahydrofolic acid; 4033-27-6/dihydrofolate; 59-30-3/Folic Acid; EC, IGF Type 1

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