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gamma-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate

Authors
Kim, SE (Kim, S-E)Cole, PD (Cole, P. D.)Cho, RC (Cho, R. C.)Ly, A (Ly, A.)Ishiguro, L (Ishiguro, L.)Sohn, KJ (Sohn, K-J)Croxford, R (Croxford, R.)Kamen, BA (Kamen, B. A.)Kim, YI (Kim, Y-I)
Issue Date
Oct-2013
Publisher
NATURE PUBLISHING GROUP
Citation
BRITISH JOURNAL OF CANCER, v.109, no.8, pp 2175 - 2188
Pages
14
Journal Title
BRITISH JOURNAL OF CANCER
Volume
109
Number
8
Start Page
2175
End Page
2188
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/147412
DOI
10.1038/bjc.2013.579
ISSN
0007-0920
1532-1827
Abstract
Background: gamma-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect. Methods: We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo. Results: Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally in
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생활과학대학 (식품영양학과)
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