Klimowicz Alexander C, Bisson Sabine A, Hans Karm, Long Elizabeth M, Hansen Henrik C, Robbins Stephen M
Southern Alberta Cancer Research Institute, Department of Oncology, The University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada T2N-4N1.
Mol Cancer Ther. 2009 Mar;8(3):602-14. doi: 10.1158/1535-7163.MCT-08-0891. Epub 2009 Mar 3.
Piceatannol is a naturally occurring bioactive stilbene with documented antileukemic properties. It has been extensively used as a Syk-selective protein tyrosine kinase inhibitor for the study of various signaling pathways. Herein, we show that the hydroxystilbene, piceatannol, and related catechol ring-containing compounds are able to induce the loss of the Cbl family of proteins. Normal cellular Cbl-regulatory mechanisms were not involved in this process. Screening of a small library of piceatannol-like compounds indicated that aromaticity and a catechol ring were required for the induction of Cbl loss. Further examination of these two chemical properties showed that the oxidative conversion of the catechol ring of piceatannol into a highly reactive O-benzoquinone was the cause of piceatannol-induced Cbl loss. Characterization of the Cbl selectivity of piceatannol-induced protein loss revealed that this compound was also able to induce the functional loss of specific Cbl-associated proteins involved in signaling pathways commonly associated with cancer. This work uncovers a new, piceatannol-dependent effect and shows a novel way in which this phenomenon can be exploited to inhibit disease-associated signaling pathways.
白皮杉醇是一种天然存在的具有抗白血病特性的生物活性芪类化合物。它已被广泛用作Syk选择性蛋白酪氨酸激酶抑制剂，用于研究各种信号通路。在此，我们表明羟基芪类化合物白皮杉醇以及相关的含儿茶酚环的化合物能够诱导Cbl家族蛋白的缺失。正常细胞的Cbl调节机制不参与此过程。对一小类白皮杉醇样化合物的筛选表明，芳香性和儿茶酚环是诱导Cbl缺失所必需的。对这两种化学性质的进一步研究表明，白皮杉醇儿茶酚环氧化转化为高反应性的邻苯醌是白皮杉醇诱导Cbl缺失的原因。对白皮杉醇诱导的蛋白缺失的Cbl选择性进行表征发现，该化合物还能够诱导参与通常与癌症相关的信号通路的特定Cbl相关蛋白的功能缺失。这项工作揭示了一种新的、依赖于白皮杉醇的效应，并展示了一种利用这种现象抑制疾病相关信号通路的新方法。
