Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53
- 作者：Michelle Martinez-Rivera1 ; Zahid H. Siddik ; zsiddik@mdanderson.org
- 关键词：ALL ; acute lymphocytic leukemia ; APAF-1 ; apoptotic protease-activating factor 1 ; AIF ; apoptosis-inducing factor ; ATM ; ataxia telangiectasia mutated ; ATR ; ataxia telangiectasia and Rad3-related ; CBP ; cAMP-response element-binding protein-binding protein ; C
- 刊名：Biochemical Pharmacology
- 出版年：2012
- 期刊代码：2_00062952
- 类别：pha
- 出版时间：15 April, 2012
- 卷：83
- 期：8
- 页码：1049-1062
- 文件大小：536 K
摘要
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 鈭?0%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 鈥済ain-of-resistance鈥?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.