Par-4 dependent modulation of cellular -catenin by medicinal plant natural product derivative 3-azido Withaferin A
Par-4 dependent modulation of cellular -catenin by medicinal plant natural product derivative 3-azido Withaferin A
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DOI：
10.1002/mc.22328
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发表时间：
2016-05-01
影响因子：
4.6
通讯作者：
Goswami, Anindya
中科院分区：
文献类型：
--
作者：
Amin, Hina;Nayak, Debasis;Goswami, Anindya
在这里，我们提供的证据表明，天然产物衍生物 3-叠氮基 Withaferin A (3-AWA) 通过调节 β-catenin 定位及其在前列腺和乳腺癌细胞中的转录活性来消除 EMT 和侵袭。这项研究首次揭示了 3-AWA 处理持续隔离核 β 连环蛋白并增强其细胞质库，这通过降低这些细胞中 β 连环蛋白转录活性来证明。此外，3-AWA 治疗引发了促凋亡细胞内 Par-4 的强烈诱导，减弱了 Akt 活性并拯救了 Phospho-GSK3（由 Akt 提供）以促进 β-catenin 不稳定。此外，我们的体外研究表明，3-AWA 治疗可放大 E-钙粘蛋白表达，同时急剧下调 c-Myc 和细胞周期蛋白 D1 蛋白。引人注目的是，通过 siRNA 敲低内源性 Par-4 强调了 3-AWA 介导的核 β 连环蛋白抑制是 Par-4 依赖性的，并且通过 Bcl-2 或 Ras 转染抑制 Par-4 活性，恢复了核 β 连环蛋白水平，表明 Par-4 介导的 β 连环蛋白调节不是混杂的。体内结果进一步证明3-AWA是肿瘤生长的有效抑制剂，免疫组织化学研究表明，与正常乳腺组织相比，乳腺癌组织中总-连环蛋白表达增加，磷酸-连环蛋白和Par-4表达减少，表明Par-4和-连环蛋白在正常和癌症条件下相互调节并呈负相关。因此，在多种癌症中，3-AWA 对细胞内 Par-4 的战略性调节可能是控制癌细胞转移的有效工具。最后，本报告提出了一种通过 3-AWA 诱导的 Par-4 蛋白控制失调的 -catenin 信号传导的新方法。 (c) 2015 年 Wiley 期刊公司。
Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating -catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear -catenin and augmented its cytoplasmic pool as evidenced by reducing -catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3 (by Akt) to promote -catenin destabilization. Further, our in vitro studies demonstrate that 3-AWA treatment amplified E-cadherin expression along with sharp downregulation of c-Myc and cyclin D1 proteins. Strikingly, endogenous Par-4 knock down by siRNA underscored 3-AWA mediated inhibition of nuclear -catenin was Par-4 dependent and suppression of Par-4 activity, either by Bcl-2 or by Ras transfection, restored the nuclear -catenin level suggesting Par-4 mediated -catenin regulation was not promiscuous. In vivo results further demonstrated that 3-AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total -catenin and decreased expression of phospho--catenin and Par-4 in breast cancer tissues as compared to normal breast tissue suggesting Par-4 and -catenin proteins are mutually regulated and inversely co-related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par-4 by 3-AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Conclusively, this report puts forward a novel approach of controlling deregulated -catenin signaling by 3-AWA induced Par-4 protein. (c) 2015 Wiley Periodicals, Inc.