TAILIEUCHUNG - Báo cáo khoa học: Modulation of IMPDH2, survivin, topoisomerase I and vimentin increases sensitivity to methotrexate in HT29 human colon cancer cells

We determined differentially expressed genes in HT29 human colon cancer cells, both after short treatment with methotrexate (MTX) and after the resistance to MTX had been established. Screening was performed using Atlas Human Cancer cDNA arrays. The analysis was carried out using Atlasimage software. Among the differen-tially expressed genes we chose for further validation were inosine mono-phosphate dehydrogenase type II (IMPDH2), inosine monophosphate cyclohydrolase and survivin as up-regulated genes, and topoisomerase I (TOP1) and vimentin as down-regulated genes. . | iFEBS Journal Modulation of IMPDH2 survivin topoisomerase I and vimentin increases sensitivity to methotrexate in HT29 human colon cancer cells Silvia Penuelas Veronique Noe and Carlos J. Ciudad Department of Biochemistry and Molecular Biology Schoolof Pharmacy University of Barcelona Spain Keywords IMPDH2 methotrexate survivin TOP1 vimentin Correspondence C. J. Ciudad Departament de Bioquimica Biologia Molecular Facultat de Farmacia Universitat de Barcelona Av. Diagonal643 E-08028 Barcelona Spain Fax 34 93 402 4520 Tel 34 93 403 4455 E-mail cciudad@ Received 3 November 2004 accepted 26 November 2004 doi We determined differentially expressed genes in HT29 human colon cancer cells both after short treatment with methotrexate MTX and after the resistance to MTX had been established. Screening was performed using Atlas Human Cancer cDNA arrays. The analysis was carried out using Atlas IMAGE and GENESPRING software. Among the differentially expressed genes we chose for further validation were inosine monophosphate dehydrogenase type II IMPDH2 inosine monophosphate cyclohydrolase and survivin as up-regulated genes and topoisomerase I TOP1 and vimentin as down-regulated genes. Changes in mRNA levels were validated by quantitative RT-PCR. Additionally functional analyses were performed inhibiting the products of the selected genes or altering their expression to test if these genes could serve as targets to modify MTX cytotoxicity. Inhibition of IMPDH or TOP1 activity antisense treatment against survivin or overexpression of vimentin sensitized resistant HT29 cells to MTX. Therefore these proteins could constitute targets to develop modulators in MTX chemotherapy. Methotrexate MTX is a 4-amino 10-methyl analog of folic acid that inhibits dihydrofolate reductase DHFR a key enzyme of the folate cycle and the one carbone unit metabolism 1-3 . MTX was one of the first antimetabolite drugs developed and even now continues .

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