HCT116 cells deficient in p21Waf1 are hypersensitive to tyrosine kinase inhibitors and adriamycin through a mechanism unrelated to p21 and dependent on p53

被引:17
作者
Ferrandiz, Nuria [1 ,2 ]
Martin-Perez, Jorge [3 ]
Blanco, Rosa [1 ,2 ]
Donertas, Derya [1 ,2 ]
Weber, Axel [4 ]
Eilers, Martin [4 ]
Dotto, Paolo [5 ]
Dolores Delgado, M. [1 ,2 ]
Leon, Javier [1 ,2 ]
机构
[1] Univ Cantabria, Dpto Biol Mol, CSIC, IDICAN,Fac Med, Santander 39011, Spain
[2] Univ Cantabria, Canc Mol Biol Grp, Inst Biomed & Biotecnol Cantabria, CSIC,IDICAN, Santander 39011, Spain
[3] CSIC, Madrid, Spain
[4] Univ Marburg, Inst Tumor Biol, Marburg, Germany
[5] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA
关键词
p53; Adriamycin; Imatinib; Gefitinib; Apoptosis; HCT116; Myc; COLON-CARCINOMA CELLS; TUMOR-FORMATION; GENETIC DISSECTION; CYCLE CONTROL; CANCER-CELLS; IN-VIVO; APOPTOSIS; P21(CIP1); INACTIVATION; SUPPRESSION;
D O I
10.1016/j.dnarep.2008.12.001
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
p21(Waf1) (p21) was described as a cyclin-dependent kinase inhibitor, but other p21 activities have subsequently been described, including its ability to inhibit apoptosis in some models. Comparative work on the human colon cancer isogenic cell lines HCT116 and HCT116p21(-/-) led to the proposal that p21 protects colon cancer cells against apoptosis by genotoxic drugs. We asked whether p21 also protected from cell death induced by non-genotoxic drugs, such as tyrosine kinase inhibitors. We found that p21-deficient cells were dramatically more sensitive towards imatinib and gefitinib than parental cells. Interestingly, HCT116p21(-/-) also showed higher basal activity of protein kinases as c-Abl, c-Src, and Akt. We generated HCT116p21(-/-) sublines with inducible p21 expression and found that p21 did not rescue the hypersensitivity to imatinib. Moreover, down-regulation of p21 by enforced c-Myc expression or by p21 siRNA did not sensitize parental HCF116 cells. We found that, in HCT116p21(-/-) cells, p53showed higher stability, higher transcriptional activity and phosphorylation in serines associated with p53 activity. Furthermore, silencing of p53 with siRNA and inactivation of p53 with a dominant negative mutant rescued the hypersensitive response to kinases inhibitors, 5-fluorouracil and adriamycin in HCT116p21(-/-) cells. Consistently, HCT116p53(-/-) cells are more resistant to imatinib than parental cells, suggesting that imatinib activity is partly dependent on p53 in colon cancer cells. We conclude that high p53 activity, rather than p21 deficiency, is the mechanism responsible for hypersensitivity to drugs of HCT116p21(-/-) cells. Therefore the role of p21 on apoptosis of HCT116 colon cancer cells should be re-evaluated. (C) 2008 Elsevier B.V. All rights reserved.
引用
收藏
页码:390 / 399
页数:10
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