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Carcinogenesis Advance Access published online on December 16, 2005
Carcinogenesis, doi:10.1093/carcin/bgi312
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received July 4, 2005
Revised September 10, 2005
Accepted December 11, 2005

CANCER BIOLOGY

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

Petar Novakovic 1, Joanne M. Stempak 2, Kyoung-Jin Sohn 3, and Young-In Kim 4 *

1 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
2 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
3 Department of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8
4 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada, M5S 1A8; Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 1A8; Department of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8; Division of Gastroenterology, St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1W8

* To whom correspondence should be addressed.
Young-In Kim, E-mail: youngin.kim{at}utoronto.ca


  Abstract

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 7 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 4 cell lines.

Keywords: Folate; chemotherapy; colon cancer; apoptosis.
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