Molecular Pathways Molecular Pathways : Regulation and Therapeutic Implications of Multidrug Resistance
Molecular Pathways Molecular Pathways : Regulation and Therapeutic Implications of Multidrug Resistance
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发表时间：
2012
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通讯作者：
Kevin G. Chen;B. Sikic
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作者：
Kevin G. Chen;B. Sikic
多药转运体是人类肿瘤多药耐药的主要机制。ABCB1(Mdr1)基因编码一种功能齐全的跨膜转运蛋白，称为P-糖蛋白(P-gp)，在许多正常人体组织和肿瘤中都有表达。P-gp在药物的分布和排泄中起重要作用，并参与肿瘤的内在和获得性耐药。ABCB1的表达调控是复杂的，在临床环境中还没有得到很好的研究。在这篇综述中，我们阐明了调控ABCB1表达和肿瘤多药耐药发展的分子信号和表观遗传相互作用。我们专注于ABCB1的获得性表达，它与癌细胞的基因组不稳定性有关，包括改变染色质结构的突变事件，基因重排，以及保护基因组完整性的肿瘤抑制蛋白(例如突变的p53)的突变。此外，通过DNA去甲基化或组蛋白H3乙酰化对ABCB1近端和远上游启动子的表观遗传修饰在诱导ABCB1表达中起着关键作用。我们描述了一个分子网络，它协调导致ABCB1激活的遗传和表观遗传事件。这些机械性的见解为处理临床MDR提供了额外的翻译目标和潜在的策略。临床癌症研究；18(7)；1863-9.2012年AACR。
Multidrug transporters constitute major mechanisms of MDR in human cancers. The ABCB1 (MDR1) gene encodes a well-characterized transmembrane transporter, termed P-glycoprotein (P-gp), which is expressed in many normal human tissues and cancers. P-gp plays a major role in the distribution and excretion of drugs and is involved in intrinsic and acquired drug resistance of cancers. The regulation of ABCB1 expression is complex and has not been well studied in a clinical setting. In this review, we elucidate molecular signaling and epigenetic interactions that governABCB1 expression and thedevelopment ofMDR in cancer. We focus on acquired expression of ABCB1 that is associated with genomic instability of cancer cells, including mutational events that alter chromatin structures, gene rearrangements, and mutations in tumor suppressor proteins (e.g., mutant p53), which guard the integrity of genome. In addition, epigenetic modifications of the ABCB1 proximal and far upstream promoters by either demethylation of DNA or acetylation of histone H3 play a pivotal role in inducing ABCB1 expression. We describe a molecular network that coordinates genetic and epigenetic events leading to the activation of ABCB1. These mechanistic insights provide additional translational targets and potential strategies to deal with clinical MDR. Clin Cancer Res; 18(7); 1863–9. 2012 AACR.