Activation of phospholipase C-γ1 and translocation of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase contribute to GL-V9-induced apoptosis in human gastric cancer cells

Exp Cell Res. 2017 Jul 1;356(1):8-19. doi: 10.1016/j.yexcr.2017.03.063. Epub 2017 Apr 13.

Abstract

Gastric cancer is the most common type of tumor in developing countries and the fourth most frequently diagnosed cancer worldwide. Here, we demonstrated the apoptotic effects of GL-V9 on several human gastric cancer cells and selected MGC-803 cells to uncover the underlying mechanism. GL-V9 elevated Bax/Bcl-2 ratio, abated mitochondrial membrane potential and triggered the onset of apoptotic execution in MGC-803 cells. Our research revealed that CHOP silencing could not inhibit apoptosis, neither could it block Ca2+ release, suggesting that GL-V9-induced apoptosis was independent of CHOP. Furthermore, GL-V9 increased mitochondrial Ca2+ uptake through 1,4,5-triphosphate (IP3) receptor via the activation of phospholipase C-γ1 and the translocation of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase from nucleus to endoplasmic reticulum. Moreover, in-vivo studies indicated that GL-V9 exhibited significant MGC-803 xenografts regression in nude mice with low systemic toxicity. In conclusion, GL-V9 could induce apoptosis in gastric cancer cells, and would be a promising therapeutical agent against gastric cancer.

Keywords: Apoptosis; Ca(2+) release; GL-V9; Gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / genetics*
  • Calcium / metabolism
  • Cell Line, Tumor
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation
  • Female
  • Flavonoids / pharmacology*
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / physiology
  • PTEN Phosphohydrolase / metabolism*
  • Phospholipase C gamma / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / pathology*
  • Transcription Factor CHOP / genetics
  • Xenograft Model Antitumor Assays
  • bcl-2-Associated X Protein / metabolism

Substances

  • 5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl)butoxy)4H-chromen-4-one
  • BAX protein, human
  • DDIT3 protein, human
  • Flavonoids
  • Inositol 1,4,5-Trisphosphate Receptors
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Transcription Factor CHOP
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Phospholipase C gamma
  • Calcium