Oncosis-like Cell Death Is Induced by Berberine Through ERK1/2-mediated Impairment of Mitochondrial Aerobic Respiration in Gliomas

Biomed Pharmacother. 2018 Jun;102:699-710. doi: 10.1016/j.biopha.2018.03.132. Epub 2018 Apr 5.

Abstract

Gliomas, the most common primary malignant brain tumor, exhibit high metabolic activity. The targeting of metabolism alterations, particularly in mitochondria, is emerging as an efficient approach for curing cancers. Here, we showed that berberine, a natural compound that is used as an antibacterial agent, could reduce cellular viability and induce oncosis-like death, characterized by cell swelling, cytoplasmic vacuoles and plasma membrane blebbing, in gliomas, and that these effects were correlated with intracellular adenosine triphosphate (ATP) depletion. We also found that berberine induced autophagy as a protective effect and decreased the oxygen consumption rate (OCR), which could inhibit mitochondrial aerobic respiration by repressing phosphorylated extracellular regulated protein kinases (p-ERK1/2). Furthermore, the down-regulation of mitochondrial p-ERK1/2 by berberine inhibited aerobic respiration and led to glycolysis, an inefficient energy production pathway. In addition, berberine reduced tumor growth and inhibited Ki-67 and p-ERK1/2 expression in vivo. The results demonstrate that berberine, which represses aerobic oxidation in mitochondria and decreases their energy production efficiency, decreases metabolic activity by reducing ERK1/2 activity.

Keywords: ATP; Berberine; ERK1/2; Glioma; Oncosis.

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Aerobiosis / drug effects
  • Animals
  • Apoptosis* / drug effects
  • Autophagy / drug effects
  • Berberine / chemistry
  • Berberine / pharmacology*
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / pathology*
  • Brain Neoplasms / ultrastructure
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cell Respiration / drug effects
  • Cell Survival / drug effects
  • Glioma / enzymology*
  • Glioma / pathology*
  • Glioma / ultrastructure
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Rats, Wistar
  • Vacuoles / drug effects
  • Vacuoles / metabolism
  • Vacuoles / ultrastructure
  • Xenograft Model Antitumor Assays

Substances

  • Berberine
  • Adenosine Triphosphate