Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation.
Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation.
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DOI：
10.1038/cddis.2015.38
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发表时间：
2015-02-26
影响因子：
9
通讯作者：
Sayers TJ
中科院分区：
文献类型：
--
作者：
Henrich CJ;Brooks AD;Erickson KL;Thomas CL;Bokesch HR;Tewary P;Thompson CR;Pompei RJ;Gustafson KR;McMahon JB;Sayers TJ
Withanoprene，一种来自秘鲁酸浆的甾体内酯，被发现对肾癌细胞和许多其他人类癌细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）介导的凋亡具有高度活性。Withanolide是鉴定的五种TRAIL致敏性withanolides中最有效和毒性最小的，通过cFLIP蛋白水平的快速下降来增强死亡受体介导的凋亡信号传导。据报道，TRAIL敏化剂发挥作用的其他机制包括：活性氧（ROS）的产生、促凋亡蛋白和抗凋亡蛋白表达的变化、死亡受体上调、内在（线粒体）凋亡途径的激活、ER应激和蛋白酶体抑制，这些机制已被证明与TRAIL活性无关。cFLIP蛋白的丢失不是由于表达的变化，而是由于不稳定和/或聚集，表明伴侣蛋白的损伤导致降解。事实上，用肝素处理改变了许多HSP 90客户蛋白的稳定性，但具有比众所周知的HSP 90抑制剂格尔德霉素更明显的特异性。由于cFLIP已被报道为HSP 90客户端，这提供了一种潜在的新机制，使细胞对TRAIL敏感。在动物研究中证实了人肾癌细胞对TRAIL诱导的凋亡的敏感性和其缺乏毒性。由于其新颖的活性，withancaseE是一种有前途的试剂，用于分析TRAIL抗性的机制，用于理解HSP 90的功能，并用于进一步的治疗开发。与硼替佐米形成鲜明对比，硼替佐米是目前最好的TRAIL敏化剂之一，其更具体的作用机制表明毒性副作用最小。
Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects.