Effects of antisense-based folylpoly-γ-glutamate synthetase down-regulation on reduced folates and cellular proliferation in CCRF-CEM cells

Yinong Liu, K. Raghunathan, Charles Hill, Yunhua He, Marlene A. Bunni, Julio Barredo, David G. Priest

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The effect of down-regulation of folylpoly-γ-glutamate synthetase (FPGS) activity on intracellular reduced folate accumulation and cellular proliferation was examined, using an inducible antisense expression system in the human T-lymphoblastic leukemia cell line CCRF-CEM. FPGS catalyzes the addition of γ-glutamyl residues to natural folates and classical antifolates, which results in their enhanced cellular retention and increased cytotoxicity. As such, this enzyme has become a focus as a potential anticancer drug target. However, direct evidence to support this concept has been elusive. Hence, a study was undertaken using an antisense-based expression system to down-regulate FPGS activity. This inducible expression system was used to demonstrate that lower FPGS activity can lead to substantially lower intracellular folate content, which coincides with suppression of thymidylate synthesis and inhibition of cellular proliferation. Copyright (C) 1998 Elsevier Science, Inc.

Original languageEnglish (US)
Pages (from-to)2031-2037
Number of pages7
JournalBiochemical Pharmacology
Volume55
Issue number12
DOIs
StatePublished - Jun 15 1998
Externally publishedYes

Keywords

  • Antisense
  • Cellular proliferation
  • Folylpolyglutamate synthetase
  • Reduced folates

ASJC Scopus subject areas

  • Pharmacology

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