Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.
Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.
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DOI：
10.1021/acscentsci.1c00070
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发表时间：
2021-05-26
影响因子：
18.2
通讯作者：
Bernardes GJL
中科院分区：
文献类型：
--
作者：
Conde J;Pumroy RA;Baker C;Rodrigues T;Guerreiro A;Sousa BB;Marques MC;de Almeida BP;Lee S;Leites EP;Picard D;Samanta A;Vaz SH;Sieglitz F;Langini M;Remke M;Roque R;Weiss T;Weller M;Liu Y;Han S;Corzana F;Morais VA;Faria CC;Carvalho T;Filippakopoulos P;Snijder B;Barbosa-Morais NL;Moiseenkova-Bell VY;Bernardes GJL
使用计算工具来识别具有抗癌特性的天然产物的生物靶点和未知的作用模式正在获得动力。我们使用自组织图谱来解旋胡椒明（PL）的表型效应，并建立了与人类瞬时受体电位香草蛋白2 （hTRPV2）通道调节的联系。用冷冻电镜（cryo-EM）测定了pl结合的大鼠全长TRPV2通道的结构。在hTRPV2过表达的胶质母细胞瘤（GBM）中，PL与瞬时变弹性口袋结合，形成了一种新的抗癌活性模式。钙成像实验揭示了Arg539和Thr522残基在PL拮抗作用和钙内流调节TRPV2通道中的重要作用。下调hTRPV2降低了对PL的敏感性，减少了ROS的产生。对GBM患者样本的分析将hTRPV2过表达与肿瘤分级、疾病进展和不良预后联系起来。通过在可植入支架/水凝胶中加入PL进行持续的局部治疗，在两个小鼠原位GBM模型中实现了广泛的肿瘤切除和长期存活。此外，在来自GBM患者的原发肿瘤样本中，我们观察到在体外对PL的反应中恶性细胞的选择性减少。我们的研究结果建立了一个广泛适用的策略，利用数据驱动的研究假设来发现治疗癌症的新方法。我们通过计算和实验验证了TRPV2作为胡椒明的靶标，并在体内建立了变构靶标参与和胶质母细胞瘤受损进展之间的联系。
The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL ex vivo. Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer. We computationally identify and experimentally validate TRPV2 as a target for piperlongumine and establish a link between allosteric target engagement and impaired glioblastoma progression in vivo.
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DOI：
10.1002/anie.201411511
发表时间：
2015-03-16
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Akbulut Y;Gaunt HJ;Muraki K;Ludlow MJ;Amer MS;Bruns A;Vasudev NS;Radtke L;Willot M;Hahn S;Seitz T;Ziegler S;Christmann M;Beech DJ;Waldmann H
通讯作者：
Waldmann H
影响因子：
41.2
作者：
Conde J;Oliva N;Atilano M;Song HS;Artzi N
通讯作者：
Artzi N
影响因子：
4.7
作者：
Jacobs VL;Valdes PA;Hickey WF;De Leo JA
通讯作者：
De Leo JA
Piperlongumine 通过活性氧积累依赖的 JNK 和 p38 激活选择性杀死多形性胶质母细胞瘤细胞
DOI：
10.1016/j.bbrc.2013.06.042
发表时间：
2013-07-19
影响因子：
3.1
作者：
Liu, Ju Mei;Pan, Feng;Chen, Xiao Qian
通讯作者：
Chen, Xiao Qian
影响因子：
3.5
作者：
Kapoor, Shobhna;Waldmann, Herbert;Ziegler, Slava
通讯作者：
Ziegler, Slava