Folate: Friend or Foe? An investigation into the opposing roles of folate in glioma

Abstract

Survival rates in patients with glioblastoma have shown little improvement over the last 40 years due to the heterogeneity of tumours and the difficulty of specifically targeting the tumour whilst sparing surrounding healthy tissue. Altered gene methylation is often observed in glioma cells, and methylating agents such as folate may reverse aberrant methylation. Folate treatment has shown a beneficial effect, reducing risk of certain cancers (colorectal, breast, squamous cell carcinoma), whereas other studies have shown detrimental effects following folate treatment, whereby proliferation of cancer increased (mammary, prostate). The aim of this study was to investigate the opposing roles of folate in glioma. The glioma cell lines 1321N1, U87 MG and non-cancerous glial SVGp12 cells were grown in folate deficient, folic or folinic acid supplemented media and compared to standard cell culture media. Cell viability, apoptosis and cell cycle analysis along with methylation status and protein expression of the genes of interest; PTEN, FOLR1, RFC, PCFT, and MTHFR were analysed to determine differences between cell lines following treatment. Folic and folinic acid behaved differently depending on the concentration used and the cell lines treated. Low folic acid at 5 µg/ml significantly increased cell viability and protein expression levels in the U87 MG and SVGp12 cell lines, whilst the high dose of folinic acid (35 µg/ml) resulted in significant decreased cell viability, increased apoptotic activity and down regulation of the folate transporters in the 1321N1, U87 MG and SVGp12 cell lines. Folate treatment did not significantly alter cell cycle phase. Altered methylation of genes specific for folate metabolism and transport did not explain the cytotoxic effects of folate in cell lines. In conclusion folinic acid rather than folic acid supplementation should be investigated further to elucidate the mechanism of potential cytotoxic effects in glioma.