Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53.
Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53.
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DOI：
10.1016/j.bcp.2011.12.026
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发表时间：
2012-04-15
影响因子：
5.8
通讯作者：
Siddik ZH
中科院分区：
文献类型：
--
作者：
Martinez-Rivera M;Siddik ZH
化疗是癌症临床治疗的基础，肿瘤抑制因子p53在这种治疗方式中起着核心作用。该蛋白通过多种关键细胞功能促进有利的抗肿瘤药物应答，包括细胞周期停滞、衰老和凋亡。一旦p53发生突变，这些功能基本上就会停止，大约50%的癌症都会发生这种情况，一些p53突变体甚至表现出功能获得效应，这会导致更大的耐药性。然而，越来越明显的是，耐药性也见于携带野生型p53的癌症。在这篇综述中，我们讨论了野生型p53是如何失活，使细胞抗肿瘤药物。这可能通过各种机制发生，包括蛋白酶体降解的增加、翻译后修饰的缺陷和p53靶基因的下游缺陷。我们还考虑了在野生型p53癌症中观察到的耐药性可能比突变型p53癌症中观察到的耐药性大得多的证据，这对设计增加已经用野生型p53引发的耐药癌症的药物反应的策略的努力提出了更大的挑战。由于野生型p53“获得性抗性”表型的机制在很大程度上是未知的，需要协调一致的研究努力，以确定这种表型的发生的基础，并在平行的，以探讨该表型可能是野生型p53功能获得性效应的产物的可能性。这些研究对于为治疗耐药野生型p53癌症的合理治疗方法奠定基础至关重要。
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 ~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.