Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission
Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission
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DOI：
10.1074/jbc.m113.487686
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发表时间：
2013-08-16
影响因子：
4.8
通讯作者：
Tsang, Benjamin K.
中科院分区：
文献类型：
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作者：
Farrand, Lee;Byun, Sanguine;Tsang, Benjamin K.
卵巢癌（OVCA）对顺铂（CDDP）的耐药源于肿瘤抑制因子和生存信号的失调。在基因毒性攻击过程中，这些因素可受到促进细胞凋亡诱导的次级因子的影响。皮杉醇是葡萄中发现的二苯乙烯白藜芦醇的天然代谢物，由其母体化合物通过cyp1ba1p450酶转化而成。据推测，它对各种细胞靶标具有特异性作用；然而，其影响癌细胞中CDDP耐药性的能力迄今尚未得到研究。在这里，我们发现皮杉醇是OVCA中CDDP敏感性的有效增强剂，这种作用是通过调节化疗耐药的几个主要决定因素来实现的。皮杉醇增强p53介导的促凋亡蛋白NOXA的表达，通过泛素-蛋白酶体途径增加XIAP的降解，并增强caspase-3的激活。这种反应与drp1依赖性线粒体分裂的增加有关，从而更有效地诱导细胞凋亡。使用小鼠OVCA模型进行的体内研究表明，与单独使用任何一种药物治疗相比，当小鼠同时使用皮杉醇和CDDP治疗时，许多这些变化与肿瘤重量的总体减少有关。综上所示，这些发现证明了皮杉醇在OVCA中增强CDDP敏感性的潜在应用，它作用于p53、XIAP和线粒体裂变。
Resistance to cisplatin (CDDP) in ovarian cancer (OVCA) arises from the dysregulation of tumor suppressors and survival signals. During genotoxic challenge, these factors can be influenced by secondary agents that facilitate the induction of apoptosis. Piceatannol is a natural metabolite of the stilbene resveratrol found in grapes and is converted from its parent compound by the enzyme CYP1BA1 p450. It has been hypothesized to exert specific effects against various cellular targets; however, its ability to influence CDDP resistance in cancer cells has not been investigated to date. Here, we show that piceatannol is a potent enhancer of CDDP sensitivity in OVCA, and this effect is achieved through the modulation of several major determinants of chemoresistance. Piceatannol enhances p53-mediated expression of the pro-apoptotic protein NOXA, increases XIAP degradation via the ubiquitin-proteasome pathway, and enhances caspase-3 activation. This response is associated with an increase in Drp1-dependent mitochondrial fission, leading to more effective induction of apoptosis. In vivo studies using a mouse model of OVCA reveal that a number of these changes occur in association with a greater overall reduction in tumor weight when mice are treated with both piceatannol and CDDP, in comparison to treatment with either agent alone. Taken together, these findings demonstrate the potential application of piceatannol to enhance CDDP sensitivity in OVCA, and it acts on p53, XIAP, and mitochondrial fission.