| Pharmacological inhibition of cyclin dependent kinases causes p53 dependent apoptosis in renal cell carcinoma. | |
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MedLine Citation:
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PMID: 20850841 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: We evaluated the effect of roscovitine (Sigma-Aldrich®), a pharmacological inhibitor of cyclin dependent kinase, on renal cell carcinoma cell lines in vitro. MATERIALS AND METHODS: We exposed several renal cell carcinoma cell lines to roscovitine and examined apoptotic signaling pathways using immunoblotting and immunohistochemistry. RESULTS: As expected, roscovitine caused dose and time dependent inhibition of cyclin dependent kinase 2 autophosphorylation, and of cyclin dependent kinase mediated Pol II phosphorylation in the ACHN (p53-wt) and 786-O (p53 inactive) renal cell carcinoma cell lines (ATCC®). Roscovitine also induced apoptosis in each cell line within a narrow concentration range (about 10 μg/ml). Apoptosis induction was more efficient in ACHN than in 786-O cells and at least partly due to p53 activity. In ACHN cells roscovitine induced apoptosis was associated with p21 induction, and decreased Akt1, XIAP and phospho-Rb expression. These changes also depended on p53 and were not present (p21) or showed a different dose pattern (Akt1, XIAP and phospho-Rb) in 786-O cells. Partial restoration of roscovitine induced apoptosis in 786-O cells by the Mdm-2 inhibitor nutlin-3 (Sigma-Aldrich) suggests that the inactivating mutation of VHL in these cells and its destabilizing effect on p53 are responsible for the decreased sensitivity to apoptosis. CONCLUSIONS: Our data extend previous studies documenting the pro-apoptotic effect of roscovitine and to our knowledge show for the first time that this activity is restricted to a narrow dose range in renal cell carcinoma cells and partly depends on p53. Thus, roscovitine is a novel potential chemotherapy in a subset of patients with renal cell carcinoma if a narrow therapeutic window is used. These data also provide insight into the role of VHL mutation and p53 in the renal cell carcinoma response to therapeutic cyclin dependent kinase manipulation. |
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Authors:
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Tatsuto Ishimaru; Jasmine Lau; Amy L Jackson; Jaime F Modiano; Robert H Weiss |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-20 |
Journal Detail:
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Title: The Journal of urology Volume: 184 ISSN: 1527-3792 ISO Abbreviation: J. Urol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-11 Completed Date: 2010-11-02 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376374 Medline TA: J Urol Country: United States |
Other Details:
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Languages: eng Pagination: 2143-9 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Division of Nephrology, Department of Internal Medicine and Cancer Center, University of California-Davis, Davis, California 95616, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Carcinoma, Renal Cell / enzymology*, pathology* Cyclin-Dependent Kinases / antagonists & inhibitors* Kidney Neoplasms / enzymology*, pathology* Protein Kinase Inhibitors / pharmacology* Purines / pharmacology* Tumor Cells, Cultured Tumor Suppressor Protein p53 / drug effects*, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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1R01CA135401-01A1/CA/NCI NIH HHS; 5U01CA86402/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Protein Kinase Inhibitors; 0/Purines; 0/Tumor Suppressor Protein p53; 0/roscovitine; EC 2.7.11.22/Cyclin-Dependent Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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