Inonotus obliquus polysaccharides induces apoptosis of lung cancer cells and alters energy metabolism via the LKB1/AMPK axis

Int J Biol Macromol. 2020 May 15;151:1277-1286. doi: 10.1016/j.ijbiomac.2019.10.174. Epub 2019 Nov 18.

Abstract

The present study explores the mechanisms underlying the anti-cancer action of Inonotus obliquus polysaccharides (IOP). Thus, we characterized the IOP components extracted from Chaga sclerotium and, found that the extracts contained 70% polysaccharides with an average molecular weight of 4.5 × 104 Da consisting of 75% glucose. We then showed that IOP extract activated AMPK in lung cancer cells expressing LKB1, suppressed cell viability, colony-formation, and triggered cell apoptosis. In conjunction, IOP downregulated Bcl-2, upregulated Bax, and enhanced cleavage of Caspase-3 and PARP. All of these effects were prevented by treatment with Compound C, a chemical inhibitor of AMPK. IOP diminished mitochondrial membrane potential (MMP), concurrent with decreases in oxidative phosphorylation and glycolysis, which was dependent on LKB1/AMPK. Finally, IOP at a dosage of 50 mg/kg significantly inhibited allograft tumor growth of the LLC1 cells in association with increased apoptosis. Collectively, our results demonstrate that IOP acts on cancer cells through a mechanism by which AMPK triggers the apoptotic pathway via the opening of mitochondrial permeability transition pore, and reducing MMP, leading to an inhibition of ATP production. Therefore, our study provides a solid foundation for the use of IOP as a promising alternative or supplementary medicine for cancer therapy.

Keywords: AMPK; Apoptosis; Energy metabolism; Inonotus obliquus polysaccharides; Tumorigenesis.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Energy Metabolism / drug effects*
  • Fungal Polysaccharides / chemistry
  • Fungal Polysaccharides / pharmacology*
  • Humans
  • Inonotus / chemistry*
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / drug effects*

Substances

  • Antineoplastic Agents
  • Fungal Polysaccharides
  • Adenosine Triphosphate
  • STK11 protein, human
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases