10-formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells.
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.
Krupenko
Sergey A
SA
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425, USA. krupenko@musc.edu
Oleinik
Natalia V
NV
D000230:Adenocarcinoma; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000502:physiology; D005492:Folic Acid / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms; D008115:Liver Regeneration / Q000502:physiology; D008175:Lung Neoplasms; D008297:Male; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism*; D011471:Prostatic Neoplasms; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D000099295:Formyltetrahydrofolate Dehydrogenase
D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D012333:RNA, Messenger; D000099295:Formyltetrahydrofolate Dehydrogenase