Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2002 Oct 21;87(9):1027-33.
doi: 10.1038/sj.bjc.6600599.

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

A Fedier  1 , U B Ruefenacht, V A Schwarz, U Haller, D Fink
Affiliations

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

A Fedier et al. Br J Cancer. .

Abstract

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 G2/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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Antiproliferative effect to a continuous exposure to cisplatin, oxaliplatin, doxorubicin, etoposide, docetaxel, and 5-fluorouracil for Pms2+/+/p53−/− and Pms2−/−/p53−/− cells as determined by the MTT-assay. Each point represents the mean±s.d. of at least four independent experiments.
Figure 2
Figure 2
Clonogenic survival curves in response to a continuous exposure to cisplatin, doxorubicin, docetaxel, and 5-fluorouracil for the Pms2+/+/p53−/− and the Pms2−/−/p53−/− cell lines. Each point represents the mean±s.d. of at least four independent experiments.
Figure 3
Figure 3
Sensitivity to cell kill of Pms2−/−/p53−/− (open field) and Pms2+/+/p53−/− (closed field) cells in response to cisplatin (3 μM), doxorubicin (50 nM) or 5-fluorouracil (5 μM) as a function of time determined by trypan blue exclusion. Each point represents the mean±s.d. of at least four independent experiments.
Figure 4
Figure 4
Representative cell cycle phase distribution profile of the DNA content for Pms2+/+/p53−/− cells (left panel) and Pms2−/−/p53−/− cells (right panel) as a function of time (0 h, 24 h, 48 h, 72 h) in response to treatment with 1.0 μM cisplatin. 2N represent cells accumulated in G1, 4N represent cells accumulated in G2/M.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. AebiSKurdi-HaidarBGordonRCenniBZhengHFinkDChristenRDBolandCRKoiMFishelRHowellSB1996Loss of DNA mismatch repair in acquired resistance to cisplatin Cancer Res 5630873090 - PubMed
    1. BlandinoGLevineAJOrenM1999Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy Oncogene 18477485 - PubMed
    1. BrownRHirstGLGallagherWMMcIlwrathAJMargisonGPvan der ZeeAGAnthoneyDA1997hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents Oncogene 154552 - PubMed
    1. BrownMJWoutersBG1999Apoptosis, p53, and tumor cell sensitivity to anticancer agents Cancer Res 5913911399 - PubMed
    1. BunzFHwangPMTorranceCWaldmanTZhangYDillehayLWilliamsJLengauerCKinzlerKWVogelsteinB1999Disruption of p53 in human cancer cells alters the responses to chemotherapeutic agents J Clin Invest 104263269 - PMC - PubMed

Publication types

MeSH terms