Dioscin-induced autophagy mitigates cell apoptosis through modulation of PI3K/Akt and ERK and JNK signaling pathways in human lung cancer cell lines

Arch Toxicol. 2013 Nov;87(11):1927-1937. doi: 10.1007/s00204-013-1047-z. Epub 2013 Apr 4.

Abstract

Our previous study has revealed that dioscin, a compound with anti-inflammatory, lipid-lowering, anticancer and hepatoprotective effects, may induce autophagy in hepatoma cells. Autophagy is a lysosomal degradation pathway that is essential for cell survival and tissue homeostasis. In this study, the role of autophagy and related signaling pathways during dioscin-induced apoptosis in human lung cancer cells was investigated. Results from 4'-6-diamidino-2-phenylindole and annexin-V/PI double-staining assay showed that caspase-3- and caspase-8-dependent, and dose-dependent apoptoses were detected after a 24-h dioscin treatment. Meanwhile, autophagy was detected as early as 12 h after an exposure to low-dose dioscin, as indicated by an up-regulated expression of LC3-II and beclin-1 proteins. Blockade of autophagy with bafilomycin A1 or 3-methyladenine sensitized the A549 and H1299 cells to apoptosis. Treatment of A549 and H1299 cells with dioscin caused a dose-dependent increase in ERK1/2 and JNK1/2 activity, accompanied with a decreased PI3K expression and decreased phosphorylation of Akt and mTOR. Taken together, this study demonstrated for the first time that autophagy occurred earlier than apoptosis during dioscin-induced human lung cancer cell line apoptosis. Dioscin-induced autophagy via ERK1/2 and JNK1/2 pathways may provide a protective mechanism for cell survival against dioscin-induced apoptosis to act as a cytoprotective reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A5
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Diosgenin / analogs & derivatives*
  • Diosgenin / pharmacology
  • Fluorescent Antibody Technique
  • Fluorescent Dyes
  • Humans
  • Indoles
  • Lung Neoplasms / pathology*
  • MAP Kinase Kinase 4 / drug effects*
  • MAP Kinase Signaling System / drug effects*
  • Oncogene Protein v-akt / physiology*
  • Organelles / drug effects
  • Phosphatidylinositol 3-Kinases / physiology*
  • Signal Transduction / drug effects*

Substances

  • Annexin A5
  • Fluorescent Dyes
  • Indoles
  • dioscin
  • DAPI
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • MAP Kinase Kinase 4
  • Diosgenin