Berberine-induced autophagic cell death by elevating GRP78 levels in cancer cells

Oncotarget. 2017 Mar 28;8(13):20909-20924. doi: 10.18632/oncotarget.14959.

Abstract

Berberine, an isoquinoline alkaloid extracted from Coptidis Rhizoma, has been shown to induce cancer cell autophagic death. Glucose regulated protein 78 (GRP78) is associated with stress-induced autophagy. However, the related mechanisms between berberine-induced cancer cell autophagy and GRP78 remain to be elucidated. Here, we report that berberine can induce autophagic cancer cell death by elevating levels of GRP78. These results further demonstrated that berberine enhanced GRP78 by suppression of ubiquitination / proteasomal degradation of GRP78 and activation of ATF6. Moreover, fluorescence spectrum assay revealed that berberine could bind to GRP78 and form complexes. Finally, co-IP analysis showed that the ability of GRP78 to bind to VPS34 was increased with berberine treatment. Taken together, our results suggest that berberine induces autophagic cancer cell death via enhancing GRP78 levels and the ability of GRP78 to bind to VPS34.

Keywords: GRP78; VPS34; autophagy; berberine; cancer cell death.

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / metabolism
  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Berberine / pharmacology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Proliferation / drug effects
  • Class III Phosphatidylinositol 3-Kinases / genetics
  • Class III Phosphatidylinositol 3-Kinases / metabolism
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Tumor Cells, Cultured

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Biomarkers, Tumor
  • Heat-Shock Proteins
  • Berberine
  • Class III Phosphatidylinositol 3-Kinases
  • molecular chaperone GRP78