Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells

Robert C. Cho, Peter D. Cole, Kyoung Jin Sohn, Gregory Gaisano, Ruth Croxford, Barton A. Kamen, Young In Kim

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Folylpolyglutamyl synthase (FPGS) converts intracellular folates and antifolates to polyglutamates. Polyglutamylated folates and antifolates are retained in cells longer and are better substrates than their monoglutamate counterparts for enzymes involved in one-carbon transfer. FPGS modulation affects the chemosensitivity of cancer cells to antifolates, such as methotrexate, and 5-fluorouracil (5FU) by altering polyglutamylation of antifolates and specific target intracellular folate cofactors. However, this effect may be counterbalanced by FPGS modulation-induced changes in polyglutamylation of other intracellular folate cofactors and total intracellular folate pools. We generated an in vitro model of FPGS overexpression and inhibition in breast cancer cells by stably transfecting human MDA-MB-435 breast cancer cells with the sense FPGS cDNA or FPGS-targeted small interfering RNA, respectively, and investigated the effects of FPGS modulation on chemosensitivity to 5FU and methotrexate. FPGS modulation-induced changes in polyglutamylation of both antifolates and folate cofactors and in intracellular folate pools affected chemosensitivity of breast cancer cells to pemetrexed and trimetrexate whose cytotoxic effects do or do not depend on polyglutamylation, respectively, in a predictable manner. However, the effects of FPGS modulation on the chemosensitivity of breast cancer cells to 5FU and methotrexate seem to be highly complex and depend not only on polyglutamylation of a specific target intracellular folate cofactor or methotrexate, respectively, but also on total intracellular folate pools and polyglutamylation of other intracellular folate cofactors. Whether or not FPGS modulation may be an important clinical determinant of chemosensitivity of breast cancer cells to 5FU and methotrexate-based chemotherapy needs further exploration.

Original languageEnglish (US)
Pages (from-to)2909-2920
Number of pages12
JournalMolecular Cancer Therapeutics
Volume6
Issue number11
DOIs
StatePublished - Nov 1 2007

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Folic Acid
Breast Neoplasms
Folic Acid Antagonists
Methotrexate
Fluorouracil
Pemetrexed
Trimetrexate
Polyglutamic Acid
Small Interfering RNA
Carbon
Complementary DNA
Drug Therapy
Enzymes

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Cho, R. C., Cole, P. D., Sohn, K. J., Gaisano, G., Croxford, R., Kamen, B. A., & Kim, Y. I. (2007). Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells. Molecular Cancer Therapeutics, 6(11), 2909-2920. https://doi.org/10.1158/1535-7163.MCT-07-0449

Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells. / Cho, Robert C.; Cole, Peter D.; Sohn, Kyoung Jin; Gaisano, Gregory; Croxford, Ruth; Kamen, Barton A.; Kim, Young In.

In: Molecular Cancer Therapeutics, Vol. 6, No. 11, 01.11.2007, p. 2909-2920.

Research output: Contribution to journalArticle

Cho, Robert C. ; Cole, Peter D. ; Sohn, Kyoung Jin ; Gaisano, Gregory ; Croxford, Ruth ; Kamen, Barton A. ; Kim, Young In. / Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 11. pp. 2909-2920.
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