Blocking autophagy enhances the apoptotic effect of 18β-glycyrrhetinic acid on human sarcoma cells via endoplasmic reticulum stress and JNK activation

Cell Death Dis. 2017 Sep 21;8(9):e3055. doi: 10.1038/cddis.2017.441.

Abstract

Sarcoma, a rare form of cancer, is unlike the much more common carcinomas as it occurs in a distinct type of tissue. The potent antitumor effects of 18β-glycyrrhetinic acid (GA), a novel naturally derived agent, have been demonstrated in various cancers. However, the effect of GA on human sarcoma, and the underlying mechanisms, remain to be elucidated. In the current study, we show that GA inhibits sarcoma cell proliferation by inducing G0/G1-phase arrest. Exposure to GA resulted in the activation of caspase-3, -8, and -9, indicating that GA induced apoptosis through both extrinsic and intrinsic pathways. In addition, the autophagy pathway, characterized by the conversion of LC3-I to LC3- II, was activated, resulting in increased Beclin-1 protein levels, decreased p62 expression, and stimulation of autophagic flux. The present findings showed that GA stimulated autophagy by inducing endoplasmic reticulum (ER) stress via the IRE1-JNK pathway. Our data supported the prosurvival role of GA-induced autophagy when the autophagy pathway was blocked with specific chemical inhibitors. Finally, GA markedly reduced sarcoma growth, with little organ-related toxicity, in vivo. The present results suggest that the combination of GA with a specific autophagy inhibitor represents a promising therapeutic approach for the treatment of sarcoma.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoribonucleases / metabolism
  • Enzyme Activation / drug effects
  • Female
  • G1 Phase / drug effects
  • Glycyrrhetinic Acid / analogs & derivatives*
  • Glycyrrhetinic Acid / pharmacology
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Protective Agents / pharmacology
  • Protein Serine-Threonine Kinases / metabolism
  • Resting Phase, Cell Cycle / drug effects
  • Sarcoma / enzymology*
  • Sarcoma / pathology*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • Protective Agents
  • 18alpha-glycyrrhetinic acid
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Endoribonucleases
  • Glycyrrhetinic Acid