Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo.
Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo.
复制标题
HSP90的氧化抑制会破坏超副酮复合物，并在体外和体内减弱胰腺腺癌。
DOI：
10.1002/ijc.27687
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发表时间：
2013-02-01
影响因子：
6.4
通讯作者：
Mandal, Chitra
中科院分区：
文献类型：
--
作者：
Sarkar, Sayantani;Dutta, Devawati;Samanta, Suman Kumar;Bhattacharya, Kaushik;Pal, Bikas Chandra;Li, Jinping;Datta, Kaustubh;Mandal, Chhabinath;Mandal, Chitra
胰腺癌几乎总是致命的，部分原因是诊断延迟、预后差、进展快和化疗耐药。致癌蛋白由Hsp90稳定，使其成为潜在的治疗靶点。我们研究了氧化应激介导的Hsp90功能障碍，以及咔唑生物碱Mahanine对其伴侣活性的抑制，作为胰腺癌的战略治疗。Mahanine通过细胞凋亡表现出对几种胰腺癌细胞株的抗增殖活性。它诱导MIAPaCa-2细胞内活性氧簇(ROS)的早期积累，导致Hsp90的硫醇氧化、聚集和功能障碍。N-乙酰-L-半胱氨酸可阻止马哈宁诱导的ROS聚集、HSP90聚集、客户蛋白降解和细胞死亡。作为ROS产生的结果，Mahanine破坏了MIAPaCa-2中的Hsp90-CDC37复合体。MG132可恢复客户蛋白，提示泛素化蛋白降解途径可能起作用。表面等离子体共振谱研究表明，马哈宁与重组Hsp90的相互作用速度在几秒内。分子动力学模拟表明其与Hsp90的相互作用较弱。然而，在早期没有观察到Hsp90-CDC37复合体的破坏，因此排除了马哈宁直接破坏复合体的可能性。它不会阻碍Hsp90的ATP结合口袋。Mahanine还减少了癌细胞的体外迁移和管状形成。此外，它还能抑制裸鼠原位胰腺肿瘤的生长。综上所述，这些结果为马哈宁诱导的ROS介导的Hsp90伴侣活性失稳，导致Hsp90-CDC37中断导致细胞凋亡提供了证据，表明它可能成为胰腺癌的特异性靶点。
Pancreatic cancer is almost always fatal, in part because of its delayed diagnosis, poor prognosis, rapid progression and chemoresistance. Oncogenic proteins are stabilized by the Hsp90, making it a potential therapeutic target. We investigated the oxidative stress-mediated dysfunction of Hsp90 and the hindrance of its chaperonic activity by a carbazole alkaloid, mahanine, as a strategic therapeutic in pancreatic cancer. Mahanine exhibited antiproliferative activity against several pancreatic cancer cell lines through apoptosis. It induced early accumulation of reactive oxygen species (ROS) leading to thiol oxidation, aggregation and dysfunction of Hsp90 in MIAPaCa-2. N-acetyl-l-cysteine prevented mahanine-induced ROS accumulation, aggregation of Hsp90, degradation of client proteins and cell death. Mahanine disrupted Hsp90-Cdc37 complex in MIAPaCa-2 as a consequence of ROS generation. Client proteins were restored by MG132, suggesting a possible role of ubiquitinylated protein degradation pathway. Surface plasmon resonance study demonstrated that the rate of interaction of mahanine with recombinant Hsp90 is in the range of seconds. Molecular dynamics simulation showed its weak interactions with Hsp90. However, no disruption of the Hsp90-Cdc37 complex was observed at an early time point, thus ruling out that mahanine directly disrupts the complex. It did not impede the ATP binding pocket of Hsp90. Mahanine also reduced in vitro migration and tube formation in cancer cells. Further, it inhibited orthotopic pancreatic tumor growth in nude mice. Taken together, these results provide evidence for mahanine-induced ROS-mediated destabilization of Hsp90 chaperone activity resulting in Hsp90-Cdc37 disruption leading to apoptosis, suggesting its potential as a specific target in pancreatic cancer.
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影响因子：
4.8
作者：
Li, NY;Ragheb, K;Robinson, JP
通讯作者：
Robinson, JP
影响因子：
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作者：
Ghoshal, Angana;Mukhopadhyay, Sumi;Mandal, Chitra
通讯作者：
Mandal, Chitra
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Ogata, Masao;Naito, Zenya;Asano, Goro
通讯作者：
Asano, Goro
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Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
5.8
作者：
Dias, N;Bailly, C
通讯作者：
Bailly, C