1. Academic Validation
  2. 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

  • Cell Death Dis. 2018 May 22;9(6):598. doi: 10.1038/s41419-018-0641-7.
Rong Zhang 1 Guobing Li 1 Qian Zhang 1 Qin Tang 1 Jingbin Huang 1 Changpeng Hu 1 Yali Liu 1 Qing Wang 1 Wuyi Liu 1 Ning Gao 2 Shiwen Zhou 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Second Affiliated Hospital, Army Medical University, 400037, Chongqing, China.
  • 2 College of Pharmacy, Army Medical University, 400038, Chongqing, China. gaoning59@tmmu.edu.cn.
  • 3 Department of Pharmacy, The Second Affiliated Hospital, Army Medical University, 400037, Chongqing, China. shiwenzhouxq@163.com.
Abstract

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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