10-formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells

Cell Growth Differ. 2002 May;13(5):227-36.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma
  • Cell Division / physiology
  • Cell Line, Transformed
  • Down-Regulation / physiology
  • Folic Acid / metabolism*
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Liver Neoplasms
  • Liver Regeneration / physiology
  • Lung Neoplasms
  • Male
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism*
  • Prostatic Neoplasms
  • RNA, Messenger / analysis
  • Tumor Cells, Cultured

Substances

  • RNA, Messenger
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • formyltetrahydrofolate dehydrogenase