Document Detail


MDM-2 antagonists induce p53-dependent cell cycle arrest but not cell death in renal cancer cell lines.
MedLine Citation:
PMID:  20953142     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Chun Chui Tsao; Paul G Corn
Publication Detail:
Type:  Journal Article     Date:  2010-12-15
Journal Detail:
Title:  Cancer biology & therapy     Volume:  10     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2011-01-13     Completed Date:  2011-07-26     Revised Date:  2013-02-05    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1315-25     Citation Subset:  IM    
Affiliation:
Department of Genitourinary Medical Oncology, University of Texas Health Science Center, Houston, TX, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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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