Degalactotigonin, a Natural Compound From Solanum Nigrum L., Inhibits Growth and Metastasis of Osteosarcoma Through GSK3β Inactivation-Mediated Repression of the Hedgehog/Gli1 Pathway

Clin Cancer Res. 2018 Jan 1;24(1):130-144. doi: 10.1158/1078-0432.CCR-17-0692. Epub 2017 Sep 26.

Abstract

Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L, has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma.Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array.Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3β. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3β inactivation.Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3β inactivation-mediated repression of the Hedgehog/Gli1 pathway. Clin Cancer Res; 24(1); 130-44. ©2017 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Hedgehog Proteins / metabolism*
  • Humans
  • Mice
  • Osteosarcoma / drug therapy
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Saponins / chemistry
  • Saponins / pharmacology*
  • Signal Transduction / drug effects*
  • Solanum nigrum / chemistry*
  • Steroids / chemistry
  • Steroids / pharmacology*
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays
  • Zinc Finger Protein GLI1 / metabolism*

Substances

  • Antineoplastic Agents, Phytogenic
  • GLI1 protein, human
  • Hedgehog Proteins
  • Saponins
  • Steroids
  • Zinc Finger Protein GLI1
  • degalactotigonin
  • Glycogen Synthase Kinase 3 beta