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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Adenine Nucleotide Translocator 1
  • Alkaloids
  • Peptidyl-Prolyl Isomerase F
  • 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