| MDM-2 antagonists induce p53-dependent cell cycle arrest but not cell death in renal cancer cell lines. | |
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MedLine Citation:
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PMID: 20953142 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Renal cell cancers (RCC) are notoriously resistant to chemotherapy and radiotherapy. While mutations of the p53 tumor suppressor gene frequently contribute to therapy resistance in other epithelial cancers, p53 mutations are relatively rare in RCC. To date, there is conflicting evidence as to whether p53 signaling and function are otherwise proficient or defective in tumors with wild-type p53. In this study, we assayed p53 function in a series of RCC cell lines and normal proximal epithelial tubule cells using two different MDM-2 antagonists, Nutlin-3a and MI-219. Most cell lines with wild-type p53 responded to MDM-2 antagonists as evidenced by induction of p53 and its target gene p21. RCC cell lines treated with MDM-2 antagonists consistently accumulated in the G2/M phase of the cell cycle and this event was associated with inhibition of proliferation in RCC cell lines but not in normal proximal epithelial tubule cells. MDM-2 antagonists did not induce significant cell death in RCC cell lines, even with induction of p53-dependent pro-apoptotic genes. In contrast, MDM-2 antagonists caused significant cell death in LNCaP prostate adenocarcinoma cells. RCC cell lines with reduced p53, either by mutation or through ectopic expression of p53 shRNA, demonstrated enhanced sensitivity to cell death following sequential treatment with DNA damage and G2/M checkpoint abrogation. Our results suggest that wild-type p53 RCC cell lines are proficient in p53-dependent cell cycle arrest but defective in p53-dependent cell death. |
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Authors:
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Chun Chui Tsao; Paul G Corn |
Publication Detail:
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Type: Journal Article Date: 2010-12-15 |
Journal Detail:
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Title: Cancer biology & therapy Volume: 10 ISSN: 1555-8576 ISO Abbreviation: Cancer Biol. Ther. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2011-01-13 Completed Date: 2011-07-26 Revised Date: 2013-02-05 |
Medline Journal Info:
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Nlm Unique ID: 101137842 Medline TA: Cancer Biol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 1315-25 Citation Subset: IM |
Affiliation:
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Department of Genitourinary Medical Oncology, University of Texas Health Science Center, Houston, TX, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis Carcinoma, Renal Cell / pathology* Cell Cycle / drug effects* Cell Death Cell Line, Tumor Cell Proliferation / drug effects Cyclin-Dependent Kinase Inhibitor p21 / genetics, metabolism* Doxorubicin / pharmacology Gene Expression Regulation, Neoplastic Genes, p53 Humans Imidazoles / pharmacology Kidney Tubules, Proximal / growth & development, metabolism Male Mutation Phosphorylation Piperazines / pharmacology Polymerase Chain Reaction Prostatic Neoplasms / metabolism, pathology Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*, metabolism RNA, Small Interfering Signal Transduction / drug effects Tumor Suppressor Protein p53 / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Cyclin-Dependent Kinase Inhibitor p21; 0/Imidazoles; 0/Piperazines; 0/RNA, Small Interfering; 0/Tumor Suppressor Protein p53; 0/nutlin 3; 23214-92-8/Doxorubicin; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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