Document Detail


Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53.
MedLine Citation:
PMID:  22227014     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chemotherapy is the bedrock for the clinical management of cancer, and the tumor suppressor p53 has a central role in this therapeutic modality. This protein facilitates favorable antitumor drug response through a variety of key cellular functions, including cell cycle arrest, senescence, and apoptosis. These functions essentially cease once p53 becomes mutated, as occurs in ∼50% of cancers, and some p53 mutants even exhibit gain-of-function effects, which lead to greater drug resistance. However, it is becoming increasingly evident that resistance is also seen in cancers harboring wild-type p53. In this review, we discuss how wild-type p53 is inactivated to render cells resistant to antitumor drugs. This may occur through various mechanisms, including an increase in proteasomal degradation, defects in post-translational modification, and downstream defects in p53 target genes. We also consider evidence that the resistance seen in wild-type p53 cancers can be substantially greater than that seen in mutant p53 cancers, and this poses a far greater challenge for efforts to design strategies that increase drug response in resistant cancers already primed with wild-type p53. Because the mechanisms contributing to this wild-type p53 "gain-of-resistance" phenotype are largely unknown, a concerted research effort is needed to identify the underlying basis for the occurrence of this phenotype and, in parallel, to explore the possibility that the phenotype may be a product of wild-type p53 gain-of-function effects. Such studies are essential to lay the foundation for a rational therapeutic approach in the treatment of resistant wild-type p53 cancers.
Authors:
Michelle Martinez-Rivera; Zahid H Siddik
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2011-12-26
Journal Detail:
Title:  Biochemical pharmacology     Volume:  83     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-12     Completed Date:  2012-05-16     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1049-62     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Apoptosis / drug effects,  genetics
Cell Cycle Checkpoints / drug effects,  genetics
Drug Resistance, Neoplasm / genetics*
Genes, p53*
Humans
Mutation
Neoplasms / drug therapy*,  genetics*,  pathology
Phosphorylation
Protein Processing, Post-Translational
Tumor Suppressor Protein p53 / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA127263/CA/NCI NIH HHS; CA160687/CA/NCI NIH HHS; CA16672/CA/NCI NIH HHS; P30 CA016672/CA/NCI NIH HHS; R01 CA127263/CA/NCI NIH HHS; R01 CA127263-05/CA/NCI NIH HHS; R01 CA160687/CA/NCI NIH HHS; R01 CA160687-01/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53
Comments/Corrections

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