title: Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2.
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.
authors.affiliation: Department of Obstetrics and Gynaecology, Division of Gynaecology, University Hospital of Zurich, CH-8091, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Fedier
authors.forename: U B
authors.initials: UB
authors.lastname: Ruefenacht
authors.forename: V A
authors.initials: VA
authors.lastname: Schwarz
authors.forename: U
authors.initials: U
authors.lastname: Haller
authors.forename: D
authors.initials: D
authors.lastname: Fink
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020137:Base Pair Mismatch; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects* / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005472:Fluorouracil / Q000494:pharmacology; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D000070976:Mismatch Repair Endonuclease PMS2; D009944:Organoplatinum Compounds / Q000494:pharmacology; D043823:Taxoids; D014343:Trypan Blue; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; C080625:taxane; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes; D014343:Trypan Blue; D005472:Fluorouracil