Targeting Chk2 improves gastric cancer chemotherapy by impairing DNA damage repair
- PDF / 685,765 Bytes
- 14 Pages / 595.276 x 790.866 pts Page_size
- 48 Downloads / 172 Views
ORIGINAL PAPER
Targeting Chk2 improves gastric cancer chemotherapy by impairing DNA damage repair A. Gutie´rrez-Gonza´lez • C. Belda-Iniesta • J. Bargiela-Iparraguirre • G. Dominguez • P. Garcı´a Alfonso • R. Perona • I. Sanchez-Perez
Published online: 28 December 2012 Ó Springer Science+Business Media New York 2012
Abstract Our results demonstrate that the addition of cisplatin after paclitaxel-induced mitotic arrest was more effective than individual treatment on gastric adenocarcinoma cells (MKN45). However, the treatment did not induce benefits in cells derived from lymph node metastasis (ST2957). Time-lapse microscopy revealed that cell death was caused by mitotic catastrophe and apoptosis induction, as the use of the caspase inhibitor z-VAD-fmk decreased cell death. We propose that the molecular
A. Gutie´rrez-Gonza´lez J. Bargiela-Iparraguirre I. Sanchez-Perez Department of Biochemistry, School of Medicine, UAM, Madrid, Spain A. Gutie´rrez-Gonza´lez J. Bargiela-Iparraguirre R. Perona I. Sanchez-Perez (&) Biomedical Research Institute of Madrid, Madrid CSIC/UAM, C/Arturo Duperier 4, 28029 Madrid, Spain e-mail: [email protected] C. Belda-Iniesta Thoracic, Head & Neck and Brain Oncology Unit, CIOCC Centro integral Oncolo´gico Clara Campal. GHM Grupo Hospital de Madrid, Madrid, Spain C. Belda-Iniesta R. Perona Biomarkers and Experimental Therapeutics Group, IdiPAZ, University Hospital La Paz, Madrid, Spain G. Dominguez Department of Medical Oncology, University Hospital Puerta de Hierro, UAM, Madrid, Spain P. Garcı´a Alfonso Department of Medical Oncology, Gregorio Maran˜on Hospital, Madrid, Spain R. Perona CIBER on Rare Diseases (CIBERER), Valencia, Spain
mechanism mediating this cell fate is a slippage suffered by these cells, given that our Western blot (WB) analysis revealed premature cyclin B degradation. This resulted in the cell exiting from mitosis without undergoing DNA damage repair, as demonstrated by the strong phosphorylation of H2AX. A comet assay indicated that DNA repair was impaired, and Western blotting showed that the Chk2 protein was degraded after sequential treatment (paclitaxelcisplatin). Based on these results, the modulation of cell death during mitosis may be an effective strategy for gastric cancer therapy. Keywords response
Cancer Mitosis Cisplatin DNA damage
Abbreviations CDDP Cisplatin PXL Paclitaxel SAC Spindle assembly checkpoint DDR DNA damage response DSBs Double strand breaks ATM Ataxia-telangiectasia mutated ATR ATM- and Rad3-related cH2AX Phosphorylated H2AX CIN Chromosome instability BRCA1 Breast cancer 1
Introduction Gastric cancer (GC) remains one of the leading causes of cancer mortality worldwide, although its incidence has been decreasing in recent years. Recent epidemiologic studies estimate that approximately 0.9 million cases of GC
123
348
are diagnosed annually worldwide. In more than half of all cases, the disease has advanced by the time of diagnosis. Despite potentially curative resection, only 45 % of patients will be free of diseas
Data Loading...
