Triptolide suppresses the growth and metastasis of non-small cell lung cancer by inhibiting β-catenin-mediated epithelial-mesenchymal transition

Acta Pharmacol Sin. 2021 Sep;42(9):1486-1497. doi: 10.1038/s41401-021-00657-w. Epub 2021 Apr 23.

Abstract

Non-small cell lung cancer (NSCLC) is characterized by a high incidence of metastasis and poor survival. As epithelial-mesenchymal transition (EMT) is well recognized as a major factor initiating tumor metastasis, developing EMT inhibitor could be a feasible treatment for metastatic NSCLC. Recent studies show that triptolide isolated from Tripterygium wilfordii Hook F attenuated the migration and invasion of breast cancer, colon carcinoma, and ovarian cancer cells, and EMT played important roles in this process. In the present study we investigated the effect of triptolide on the migration and invasion of NSCLC cell lines. We showed that triptolide (0.5, 1.0, 2.0 nM) concentration-dependently inhibited the migration and invasion of NCI-H1299 cells. Triptolide treatment concentration-dependently suppressed EMT in NCI-H1299 cells, evidenced by significantly elevated E-cadherin expression and reduced expression of ZEB1, vimentin, and slug. Furthermore, triptolide treatment suppressed β-catenin expression in NCI-H1299 and NCI-H460 cells, overexpression of β-catenin antagonized triptolide-caused inhibition on EMT, whereas knockout of β-catenin enhanced the inhibitory effect of triptolide on EMT. Administration of triptolide (0.75, 1.5 mg/kg per day, ip, every 2 days) for 18 days in NCI-H1299 xenograft mice dose-dependently suppressed the tumor growth, restrained EMT, and decreased lung metastasis, as evidence by significantly decreased expression of mesenchymal markers, increased expression of epithelial markers as well as reduced number of pulmonary lung metastatic foci. These results demonstrate that triptolide suppresses NSCLC metastasis by targeting EMT via reducing β-catenin expression. Our study implies that triptolide may be developed as a potential agent for the therapy of NSCLC metastasis.

Keywords: epithelial–mesenchymal transition; invasion; metastasis; migration; non-small cell lung cancer; triptolide; β-catenin.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Diterpenes / pharmacology*
  • Epithelial-Mesenchymal Transition / drug effects*
  • Epoxy Compounds / pharmacology
  • Heterografts
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phenanthrenes / pharmacology*
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Antineoplastic Agents, Alkylating
  • Diterpenes
  • Epoxy Compounds
  • Phenanthrenes
  • beta Catenin
  • triptolide