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Start Over Author "Didion, M." Journal cancer letters
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2. Overexpression of folate binding protein alpha is one of the mechanism explaining the adaptation of HT29 cells to high concentration of methotrexate.

Author

de Nonancourt-Didion M, Guéant JL, Adjalla C, Chéry C, Hatier R, and Namour F

Subjects
Carrier Proteins genetics, Carrier Proteins metabolism, Cell Division drug effects, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Folate Receptors, GPI-Anchored, Folic Acid pharmacology, HT29 Cells metabolism, HT29 Cells physiology, Humans, Phosphatidylinositol Diacylglycerol-Lyase, Phosphoinositide Phospholipase C, Protein Binding drug effects, Protein Isoforms biosynthesis, Protein Isoforms genetics, Protein Isoforms metabolism, Tetrahydrofolate Dehydrogenase metabolism, Transcription, Genetic drug effects, Type C Phospholipases metabolism, Antimetabolites, Antineoplastic pharmacology, Carrier Proteins biosynthesis, HT29 Cells drug effects, Methotrexate pharmacology, Receptors, Cell Surface
Abstract

The human colon adenocarcinoma cell line HT29 can be adapted to 10(-7)- 10(-4) M concentrations of methotrexate (MTX). Cells adapted to 10(-4) M MTX have an enterocyte-like phenotype with DHFR gene amplification. Presently, we hypothetized that an increased expression of folate binding protein (FBP) may participate to the MTX resistance of 10(-4) MTX HT29 cells. The cDNA FBPalpha/beta-actin ratio of amplified transcripts was 4.8- and 1.5- fold higher in 10(-4) and in 10(-7) M MTX HT29 respectively, than in standard type HT29 cells. An increase of transcript level was observed when decreasing folic acid concentration. PI-PLC cleaved 7.7 times more membrane FBP in 10(-4) M than in 10(-7) M MTX and wild type HT29 cells. In contrast to 10(-7) M MTX cells, growth of 10(-4) M MTX cells was dependent on folic acid concentration and abolished at a concentration lower than 0.9 microM. In conclusion, the adaptive mechanism of HT29 cells resistant to 10(-4) M MTX is the result of the synergistic overexpression of both DHFR and FBPalpha. Overexpression of FBPalpha may be related to the enterocyte-like phenotype of the cells.

Published
2001
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