Hirsutine induces mPTP-dependent apoptosis through ROCK1/PTEN/PI3K/GSK3β pathway in human lung cancer cells.

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.

• Authors: Rong Zhang, Guobing Li, Qian Zhang, Qin Tang, Jingbin Huang, Changpeng Hu, Yali Liu, Qing Wang, Wuyi Liu, Ning Gao, Shiwen Zhou
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 6 Pg. 598 (05 22 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29789524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenine Nucleotide Translocator 1
• Alkaloids
• Cyclophilin D
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• PPIF protein, mouse
• Reactive Oxygen Species
• SLC25A4 protein, human
• Adenosine Triphosphate
• Cytochromes c
• Glycogen Synthase Kinase 3 beta
• ROCK1 protein, human
• rho-Associated Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• Cyclophilins
• hirsutine

Topics

• A549 Cells
• Adenine Nucleotide Translocator 1 (metabolism)
• Adenosine Triphosphate (metabolism)
• Alkaloids (chemistry, pharmacology)
• Animals
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cyclophilin D
• Cyclophilins (metabolism)
• Cytochromes c (metabolism)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Lung Neoplasms (metabolism, pathology, ultrastructure)
• Membrane Potential, Mitochondrial (drug effects)
• Mice, Nude
• Mitochondria (drug effects, metabolism, ultrastructure)
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Permeability Transition Pore
• Models, Biological
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays
• rho-Associated Kinases (metabolism)