| Folylpoly-gamma-glutamate synthetase (FPGS) is essential in (anti)-folate polyglutamation and intracellular retention. Folylpolyglutamates are preferred substrates for DNA methylation and synthesis, and anti folylpolyglutamates confer cytotoxicity. The present research investigated the role of folate and FPGS in the chemotherapeutics of human colon cancer cells. The effect of folate deficiency on endogenous FPGS levels, and altered FPGS levels on chemosensitivity were examined. Folate deficiency reduced FPGS expression in Caco2 and HCT116 human colon cancer cells and FPGS activity only in Caco2 cells. An in vitro model of altered FPGS levels in HCT116 cells was developed and its biochemical properties described. Sense human FPGS cDNA conferred up-regulation of FPGS expression and activity, increased intracellular folate concentration, enhanced polyglutamation, increased growth rate and enhanced chemosensitivity to 5-fluorouracil compared with antisense hFPGS cells. Collectively, these data contribute to the current understanding of the role of folate and FPGS in the chemotherapeutics of human colon cancer cells. |
