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Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels

Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of severa...

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Autores principales: Giovannetti, E, Backus, H H J, Wouters, D, Ferreira, C G, van Houten, V M M, Brakenhoff, R H, Poupon, M-F, Azzarello, A, Pinedo, H M, Peters, G J
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360080/
https://www.ncbi.nlm.nih.gov/pubmed/17339891
http://dx.doi.org/10.1038/sj.bjc.6603639
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author Giovannetti, E
Backus, H H J
Wouters, D
Ferreira, C G
van Houten, V M M
Brakenhoff, R H
Poupon, M-F
Azzarello, A
Pinedo, H M
Peters, G J
author_facet Giovannetti, E
Backus, H H J
Wouters, D
Ferreira, C G
van Houten, V M M
Brakenhoff, R H
Poupon, M-F
Azzarello, A
Pinedo, H M
Peters, G J
author_sort Giovannetti, E
collection PubMed
description Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of several genes, it may modulate TS activity, and changes in the status of p53 might be responsible for chemoresistance. Therefore, this study was aimed to investigate TS levels and sensitivity to TS inhibitors in wild-type (wt) and mutant (mt) p53 CRC cells, Lovo and WiDr, respectively, transfected with mt and wt p53. Lovo 175X2 cells (transfected with mt p53) were more resistant to 5-fluorouracil (5-FU; 2-fold), nolatrexed (3-fold), raltitrexed (3-fold) and pemetrexed (10-fold) in comparison with the wt p53 parental cells Lovo 92. Resistance was associated with an increase in TS protein expression and catalytic activity, which might be caused by the loss of the inhibitory effect on the activity of TS promoter or by the lack of TS mRNA degradation, as suggested by the reversal of TS expression to the levels of Lovo 92 cells by adding actinomycin. In contrast, Lovo li cells, characterized by functionally inactive p53, were 3-13-fold more sensitive to nolatrexed, raltitrexed and pemetrexed, and had a lower TS mRNA, protein expression and catalytic activity than Lovo 92. However, MDM-2 expression was significantly higher in Lovo li, while no significant differences were observed in Lovo 175X2 cells with respect to Lovo 92. Finally, mt p53 WiDr transfected with wt p53 were not significantly different from mt p53 WiDr cells with respect to sensitivity to TS inhibitors or TS levels. Altogether, these results indicate that changes in the status of p53, can differently alter sensitivity to TS inhibitors by affecting TS levels, depending on activity or cell line, and might explain the lack of clear correlation between mutations in p53 and clinical outcome after chemotherapy with TS inhibitors.
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spelling pubmed-23600802009-09-10 Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels Giovannetti, E Backus, H H J Wouters, D Ferreira, C G van Houten, V M M Brakenhoff, R H Poupon, M-F Azzarello, A Pinedo, H M Peters, G J Br J Cancer Translational Therapeutics Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of several genes, it may modulate TS activity, and changes in the status of p53 might be responsible for chemoresistance. Therefore, this study was aimed to investigate TS levels and sensitivity to TS inhibitors in wild-type (wt) and mutant (mt) p53 CRC cells, Lovo and WiDr, respectively, transfected with mt and wt p53. Lovo 175X2 cells (transfected with mt p53) were more resistant to 5-fluorouracil (5-FU; 2-fold), nolatrexed (3-fold), raltitrexed (3-fold) and pemetrexed (10-fold) in comparison with the wt p53 parental cells Lovo 92. Resistance was associated with an increase in TS protein expression and catalytic activity, which might be caused by the loss of the inhibitory effect on the activity of TS promoter or by the lack of TS mRNA degradation, as suggested by the reversal of TS expression to the levels of Lovo 92 cells by adding actinomycin. In contrast, Lovo li cells, characterized by functionally inactive p53, were 3-13-fold more sensitive to nolatrexed, raltitrexed and pemetrexed, and had a lower TS mRNA, protein expression and catalytic activity than Lovo 92. However, MDM-2 expression was significantly higher in Lovo li, while no significant differences were observed in Lovo 175X2 cells with respect to Lovo 92. Finally, mt p53 WiDr transfected with wt p53 were not significantly different from mt p53 WiDr cells with respect to sensitivity to TS inhibitors or TS levels. Altogether, these results indicate that changes in the status of p53, can differently alter sensitivity to TS inhibitors by affecting TS levels, depending on activity or cell line, and might explain the lack of clear correlation between mutations in p53 and clinical outcome after chemotherapy with TS inhibitors. Nature Publishing Group 2007-03-12 2007-03-06 /pmc/articles/PMC2360080/ /pubmed/17339891 http://dx.doi.org/10.1038/sj.bjc.6603639 Text en Copyright © 2007 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Translational Therapeutics
Giovannetti, E
Backus, H H J
Wouters, D
Ferreira, C G
van Houten, V M M
Brakenhoff, R H
Poupon, M-F
Azzarello, A
Pinedo, H M
Peters, G J
Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels
title Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels
title_full Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels
title_fullStr Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels
title_full_unstemmed Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels
title_short Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels
title_sort changes in the status of p53 affect drug sensitivity to thymidylate synthase (ts) inhibitors by altering ts levels
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360080/
https://www.ncbi.nlm.nih.gov/pubmed/17339891
http://dx.doi.org/10.1038/sj.bjc.6603639
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