Hirsutine induces mPTP-dependent apoptosis through ROCK1/PTEN/PI3K/GSK3β pathway in human lung cancer cells.
Hirsutine induces mPTP-dependent apoptosis through ROCK1/PTEN/PI3K/GSK3β pathway in human lung cancer cells.
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Hirsutine 通过 ROCK1/PTEN/PI3K/GSK3β 途径诱导人肺癌细胞中 mPTP 依赖性细胞凋亡。
DOI：
10.1038/s41419-018-0641-7
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发表时间：
2018-05-22
影响因子：
9
通讯作者：
Zhou S
中科院分区：
文献类型：
--
作者：
Zhang R;Li G;Zhang Q;Tang Q;Huang J;Hu C;Liu Y;Wang Q;Liu W;Gao N;Zhou S
从钩藤中提取的Hirsutine具有抗癌活性。然而，其抗肺癌活性的分子机制尚不清楚。在本研究中，我们发现，在人肺癌细胞中，毛素通过线粒体膜电位（ATP）的损失，三磷酸腺苷（ATP）耗竭，ROS的产生，以及细胞色素c的释放诱导细胞凋亡。GSK 3 β去磷酸化通过ANT 1/CypD相互作用参与Hirsutine介导的线粒体通透性转换孔（mPTP）开放。机制研究表明，阻断ROCK 1/PTEN/PI 3 K/Akt信号通路在Hirsutine介导的GSK 3 β去磷酸化和线粒体凋亡中起重要作用。我们的体内研究还表明，在A549异种移植小鼠模型中，毛素通过ROCK 1/PTEN/PI 3 K/Akt信号转导介导的GSK 3 β去磷酸化和凋亡有效地抑制肿瘤生长。总的来说，这些发现表明了一个分层模型，其中毛藤素诱导凋亡主要源于ROCK 1和PTEN的激活，PI 3 K/Akt的失活，进而导致GSK 3 β去磷酸化和mPTP开放，并最终导致caspase-3激活和凋亡。这些结果为毛素治疗肺癌提供了新的机制依据。
Hirsutine extracted from Uncaria rhynchophylla has been shown to exhibit anti-cancer activity. However, the molecular mechanism by which hirsutine exhibits anti-lung cancer activity remains unclear. In the present study, we showed that hirsutine induces apoptosis in human lung cancer cells via loss of mitochondrial membrane potential (∆ψm), adenosine triphosphate (ATP) depletion, ROS production, as well as cytochrome c release. Dephosphorylation of GSK3β is involved in hirsutine-mediated mitochondrial permeability transition pore (mPTP) opening through ANT1/CypD interaction. Mechanistic study revealed that interruption of ROCK1/PTEN/PI3K/Akt signaling pathway plays a critical role in hirsutine-mediated GSK3β dephosphorylation and mitochondrial apoptosis. Our in vivo study also showed that hirsutine effectively inhibits tumor growth in a A549 xenograft mouse model through ROCK1/PTEN/PI3K/Akt signaling-mediated GSK3β dephosphorylation and apoptosis. Collectively, these findings suggest a hierarchical model in which induction of apoptosis by hirsutine stems primarily from activation of ROCK1 and PTEN, inactivation of PI3K/Akt, leading in turn to GSK3β dephosphorylation and mPTP opening, and culminating in caspase-3 activation and apoptosis. These findings could provide a novel mechanistic basis for the application of hirsutine in the treatment of human lung cancer.
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DOI：
10.1196/annals.1420.023
发表时间：
2008-01-01
期刊：
CONTROL AND REGULATION OF TRANSPORT PHENOMENA IN THE CARDIAC SYSTEM
影响因子：
--
作者：
Juhaszova, Magdalena;Wang, Su;Sollott, Steven J.
通讯作者：
Sollott, Steven J.
影响因子：
3.4
作者：
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通讯作者：
Tanno, Masaya
影响因子：
8
作者：
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通讯作者：
Olson, M. F.
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影响因子：
6.1
作者：
Liu, Gang;Wang, Zhong-Kun;Wang, Lin
通讯作者：
Wang, Lin
影响因子：
4.1
作者：
Chirumbolo, Salvatore
通讯作者：
Chirumbolo, Salvatore