Quick Search:

uzh logo
Browse by:
bullet
bullet
bullet
bullet

Zurich Open Repository and Archive 

Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-34897

Pani, E; Stojic, L; El-Shemerly, M; Jiricny, J; Ferrari, S (2007). Mismatch repair status and the response of human cells to cisplatin. Cell Cycle, 6(14):1796-1802.

[img]
Preview
PDF
2MB

Abstract

The emergence of resistance to cisplatin is a serious drawback of cancer therapy. To help elucidate the molecular basis of this resistance, we examined matched ovarian cancer cell lines that differ in their DNA mismatch repair (MMR) status and the response to cisplatin. Checkpoint activation by cisplatin was identical in both lines. However, sensitive cells delayed S-phase transition, arrested at G(2)/M and died by apoptosis. The G(2)/M block was characterized by selective disappearance of homologous recombination (HR) proteins, which likely resulted in incomplete repair of the cisplatin adducts. In contrast, resistant cells transiently arrested at G(2)/M, maintained constant levels of HR proteins and ultimately resumed cell cycle progression. The net contribution of MMR to the cisplatin response was examined using matched semi-isogenic (HCT116+/-chr3) or strictly isogenic (293T-Lalpha(-/+)) cell lines. Delayed transition through S-phase in response to cisplatin was also observed in the MMR-proficient HCT116+chr3 cells. Unlike in the ovarian cell lines, however, both HCT116+chr3 and HCT116 permanently arrested at G(2)/M with an intact complement of HR proteins and died by apoptosis. A similar G(2)/M arrest was observed in the strictly isogenic 293T-Lalpha(-/+) cells. This confirmed that although MMR undoubtedly contributes towards the cytotoxicity of cisplatin, it is only one of several pathways that modulate the cellular response to this drug. However, our data highlighted the importance of HR to cisplatin cytotoxicity and suggested that HR status might represent a novel prognostic marker and possibly also a therapeutic target, the inhibition of which would substantially sensitize cells to cisplatin chemotherapy.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
DDC:570 Life sciences; biology
Date:2007
Deposited On:15 Jul 2010 20:10
Last Modified:28 Nov 2013 00:20
Publisher:Landes Bioscience
ISSN:1551-4005
Publisher DOI:10.4161/cc.6.14.4472
PubMed ID:17622800
Citations:Web of Science®. Times Cited: 19
Google Scholar™
Scopus®. Citation Count: 22

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page