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Cell Growth & Differentiation Vol. 13, 227-236, May 2002
© 2002 American Association for Cancer Research

10-Formyltetrahydrofolate Dehydrogenase, One of the Major Folate Enzymes, Is Down-Regulated in Tumor Tissues and Possesses Suppressor Effects on Cancer Cells1

Sergey A. Krupenko2 and Natalia V. Oleinik

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425

Our studies showed that an abundant folate enzyme, 10-formyltetrahydrofolatedehydrogenase (FDH), is strongly down-regulated in several types of cancer on both the mRNA and the protein level. Transient expression of FDH in several human prostate cancer cell lines, a hepatocarcinoma cell line, HepG2, and a lung cancer cell line, A549, suppressed proliferation and resulted in cytotoxicity. In contrast, overexpression of a catalytically inactive FDH mutant did not inhibit proliferation, which suggests that the suppressor effect of FDH is a result of its enzymatic function. Because the FDH substrate, 10-formyltetrahydrofolate, is required for de novo purine biosynthesis, we hypothesized that the inhibitory effects of FDH occur through the depletion of intracellular 10-formyltetrahydrofolate followed by the loss of de novo purine biosynthesis. The ultimate impact is diminished DNA/RNA biosynthesis. Indeed, supplementation of FDH-overexpressing cells with 5-formyltetrahydrofolate or hypoxanthine reversed the FDH growth-inhibitory effects. Hence, down-regulation of FDH in tumors is proposed to be one of the cellular mechanisms that enhance proliferation.




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