Cargando…

Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2

A large fraction of human tumours carries mutations in the p53 gene. p53 plays a central role in controlling cell cycle checkpoint regulation, DNA repair, transcription, and apoptosis upon genotoxic stress. Lack of p53 function impairs these cellular processes, and this may be the basis of resistanc...

Descripción completa

Detalles Bibliográficos
Autores principales: Fedier, A, Ruefenacht, U B, Schwarz, V A, Haller, U, Fink, D
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364320/
https://www.ncbi.nlm.nih.gov/pubmed/12434296
http://dx.doi.org/10.1038/sj.bjc.6600599
_version_ 1782153925009342464
author Fedier, A
Ruefenacht, U B
Schwarz, V A
Haller, U
Fink, D
author_facet Fedier, A
Ruefenacht, U B
Schwarz, V A
Haller, U
Fink, D
author_sort Fedier, A
collection PubMed
description A large fraction of human tumours carries mutations in the p53 gene. p53 plays a central role in controlling cell cycle checkpoint regulation, DNA repair, transcription, and apoptosis upon genotoxic stress. Lack of p53 function impairs these cellular processes, and this may be the basis of resistance to chemotherapeutic regimens. By virtue of the involvement of DNA mismatch repair in modulating cytotoxic pathways in response to DNA damaging agents, we investigated the effects of loss of Pms2 on the sensitivity to a panel of widely used anticancer agents in E1A/Ha-Ras-transformed p53-null mouse fibroblasts either proficient or deficient in Pms2. We report that lack of the Pms2 gene is associated with an increased sensitivity, ranging from 2–6-fold, to some types of anticancer agents including the topoisomerase II poisons doxorubicin, etoposide and mitoxantrone, the platinum compounds cisplatin and oxaliplatin, the taxanes docetaxel and paclitaxel, and the antimetabolite gemcitabine. In contrast, no change in sensitivity was found after treatment with 5-fluorouracil. Cell cycle analysis revealed that both, Pms2-deficient and -proficient cells, retain the ability to arrest at the G(2)/M upon cisplatin treatment. The data indicate that the concomitant loss of Pms2 function chemosensitises p53-deficient cells to some types of anticancer agents, that Pms2 positively modulates cell survival by mechanisms independent of p53, and that increased cytotoxicity is paralleled by increased apoptosis. Tumour-targeted functional inhibition of Pms2 may be a valuable strategy for increasing the efficacy of anticancer agents in the treatment of p53-mutant cancers. British Journal of Cancer (2002) 87, 1027–1033. doi:10.1038/sj.bjc.6600599 www.bjcancer.com © 2002 Cancer Research UK
format Text
id pubmed-2364320
institution National Center for Biotechnology Information
language English
publishDate 2002
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-23643202009-09-10 Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2 Fedier, A Ruefenacht, U B Schwarz, V A Haller, U Fink, D Br J Cancer Experimental Therapeutics A large fraction of human tumours carries mutations in the p53 gene. p53 plays a central role in controlling cell cycle checkpoint regulation, DNA repair, transcription, and apoptosis upon genotoxic stress. Lack of p53 function impairs these cellular processes, and this may be the basis of resistance to chemotherapeutic regimens. By virtue of the involvement of DNA mismatch repair in modulating cytotoxic pathways in response to DNA damaging agents, we investigated the effects of loss of Pms2 on the sensitivity to a panel of widely used anticancer agents in E1A/Ha-Ras-transformed p53-null mouse fibroblasts either proficient or deficient in Pms2. We report that lack of the Pms2 gene is associated with an increased sensitivity, ranging from 2–6-fold, to some types of anticancer agents including the topoisomerase II poisons doxorubicin, etoposide and mitoxantrone, the platinum compounds cisplatin and oxaliplatin, the taxanes docetaxel and paclitaxel, and the antimetabolite gemcitabine. In contrast, no change in sensitivity was found after treatment with 5-fluorouracil. Cell cycle analysis revealed that both, Pms2-deficient and -proficient cells, retain the ability to arrest at the G(2)/M upon cisplatin treatment. The data indicate that the concomitant loss of Pms2 function chemosensitises p53-deficient cells to some types of anticancer agents, that Pms2 positively modulates cell survival by mechanisms independent of p53, and that increased cytotoxicity is paralleled by increased apoptosis. Tumour-targeted functional inhibition of Pms2 may be a valuable strategy for increasing the efficacy of anticancer agents in the treatment of p53-mutant cancers. British Journal of Cancer (2002) 87, 1027–1033. doi:10.1038/sj.bjc.6600599 www.bjcancer.com © 2002 Cancer Research UK Nature Publishing Group 2002-10-21 2002-10-21 /pmc/articles/PMC2364320/ /pubmed/12434296 http://dx.doi.org/10.1038/sj.bjc.6600599 Text en Copyright © 2002 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 Experimental Therapeutics
Fedier, A
Ruefenacht, U B
Schwarz, V A
Haller, U
Fink, D
Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2
title Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2
title_full Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2
title_fullStr Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2
title_full_unstemmed Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2
title_short Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2
title_sort increased sensitivity of p53-deficient cells to anticancer agents due to loss of pms2
topic Experimental Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364320/
https://www.ncbi.nlm.nih.gov/pubmed/12434296
http://dx.doi.org/10.1038/sj.bjc.6600599
work_keys_str_mv AT fediera increasedsensitivityofp53deficientcellstoanticanceragentsduetolossofpms2
AT ruefenachtub increasedsensitivityofp53deficientcellstoanticanceragentsduetolossofpms2
AT schwarzva increasedsensitivityofp53deficientcellstoanticanceragentsduetolossofpms2
AT halleru increasedsensitivityofp53deficientcellstoanticanceragentsduetolossofpms2
AT finkd increasedsensitivityofp53deficientcellstoanticanceragentsduetolossofpms2