Journal Article

Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells

Petar Novakovic, Joanne M. Stempak, Kyoung-Jin Sohn and Young-In Kim

in Carcinogenesis

Volume 27, issue 5, pages 916-924
Published in print May 2006 | ISSN: 0143-3334
Published online December 2005 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgi312
Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells

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Folate is a B vitamin, deficiency of which appears to increase the risk of developing several malignancies including colorectal cancer. In contrast to the cancer-promoting effect of folate deficiency in normal tissues, several lines of evidence indicate that folate depletion suppresses the progression of existing neoplasms and enhance the sensitivity of cancer cells to chemotherapy. Folate mediates the transfer of one-carbon necessary for the de novo biosynthesis of purines and thymidylate, and hence is an essential factor for DNA synthesis and repair, and the maintenance of DNA integrity and stability. Folate deficiency induces DNA strand breaks, increases uracil misincorporation into DNA, impairs DNA repair and appears to induce apoptosis. Although the effects of folate depletion on DNA integrity and apoptosis and on subsequent cancer development, progression and treatment in colonic epithelial cells have been well characterized, it is largely unknown at present how folate depletion modulates specific upstream genes in apoptosis and cancer pathways that regulate these processes. We therefore investigated the effects of folate depletion on expression of genes involved in apoptosis and cancer pathways in four human colon adenocarcinoma cell lines in an in vitro model of folate deficiency. Apoptosis and cancer pathway-specific mini-microarray were used to screen for differentially expressed genes in response to folate deficiency, and the expression of seven most notably and consistently affected genes was confirmed by real time RT–PCR. Our data suggest that folate deficiency affects the expression of key genes that are related to cell cycle control, DNA repair, apoptosis and angiogenesis in a cell-specific manner. Cell-specificity in gene expression changes in response to folate deficiency is likely due to significant differences in molecular and phenotypic characteristics, growth rates and intracellular folate concentrations among the four cell lines.

Keywords: ALAS1, 5-aminolevulinate delta synthase 1; ATM, ataxia telangiectasia mutated; BAX, BCL-2 associated X protein; CDKN1A, cyclin-dependent kinase inhibitor 1-p21cip1; CTNNB1, cadherin-associated protein-β-catenin 1; MDM-2, p53 binding protein; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor

Journal Article.  6381 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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