Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line
| Autor: | Miguel Abal, Patricia de Cremoux, Marie-France Poupon, Sylvie Robine, Rui Bras-Gonçalves, Hafida Fsihi, Henri Magdelenat, Jean-Gabriel Judde, Daniel Louvard |
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| Rok vydání: | 2004 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Cancer Research Tumor suppressor gene Colorectal cancer Cyclin B Biology Irinotecan medicine.disease_cause Cyclin-dependent kinase Cyclins CDC2 Protein Kinase Roscovitine Genetics medicine Humans Enzyme Inhibitors neoplasms Molecular Biology Cyclin-dependent kinase 1 Cell Cycle Transfection medicine.disease digestive system diseases Enzyme Activation Purines Apoptosis Mutation Immunology Cancer research biology.protein Camptothecin Tumor Suppressor Protein p53 Carcinogenesis HT29 Cells medicine.drug |
| Zdroj: | Oncogene. 23:1737-1744 |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Mutations in the tumor-suppressor gene p53 have been associated with advanced colorectal cancer (CRC). Irinotecan (CPT-11), a DNA topoisomerase 1 inhibitor, has been recently incorporated to the adjuvant therapy. Since the DNA-damage checkpoint depends on p53 activation, the status of p53 might critically influence the response to CPT-11. We analysed the sensitivity to CPT-11 in the human colon cancer cell line HT29 (mut p53) and its wild-type (wt)-p53 stably transfected subclone HT29-A4. Cell-cycle analysis in synchronised cells demonstrated the activation of transfected wt-p53 and a p21(WAF1/CIP1)-dependent cell-cycle blockage in the S phase. Activated wt-p53 increased apoptosis and enhanced sensitivity to CPT-11. In p53-deficient cells, cDNA-macroarray analysis and western blotting showed an accumulation of the cyclin-dependent kinase (cdk)1/cyclin B complex. Subsequent p53-independent activation of the cdk-inhibitor (cdk-I) p21(WAF1/CIP1) prevented cell-cycle progression. Cdk1 induction was exploited in vivo to improve the sensitivity to CPT-11 by additional treatment with the cdk-I CYC-202. We demonstrate a gain of sensitivity to CPT-11 in a p53-mutated colon cancer model either by restoring wild-type p53 function or by sequential treatment with cdk-Is. Considering that mutations in p53 are among the most common genetic alterations in CRC, a therapeutic approach specifically targeting p53-deficient tumors could greatly improve the treatment outcomes. |
| Databáze: | OpenAIRE |
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