Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer

Oncol Rep. 2022 Mar;47(3):52. doi: 10.3892/or.2022.8263. Epub 2022 Jan 14.

Abstract

The interleukin 6 (IL‑6)/glycoprotein 130 (GP130)/signal transducer and activator of transcription 3 (STAT3) signalling pathway, with GP130 as an intermediate membrane receptor, is involved in the survival, metastasis, and resistance of ovarian cancer. Bazedoxifene, an FDA‑approved drug, is an inhibitor of GP130 and a selective estrogen modulator (SERM). We studied the mechanism of the combination therapy of bazedoxifene and paclitaxel in inhibiting the IL‑6‑mediated GP130/STAT3 signaling pathway in ovarian cancer. Surface plasmon resonance (SPR) was used to assess the binding of bazedoxifene to GP130. Migration, invasion, and apoptosis of ovarian cancer cells were assessed using bazedoxifene and paclitaxel. In addition, we determined the effects of bazedoxifene and paclitaxel alone or in combination on the GP130/STAT3 pathway and epithelial‑mesenchymal transition (EMT). The results revealed that the combination of bazedoxifene and paclitaxel suppressed cell viability, migration, and invasion in the ovarian cancer cells. In addition, the combination treatment increased apoptosis. Furthermore, bazedoxifene combined with paclitaxel inhibited the growth of ovarian cancer cells in a xenograft tumour model. This combination reduced STAT3 phosphorylation and suppressed gene expression and EMT. In conclusion, inhibition of GP130/STAT3 signalling and EMT via a combination of bazedoxifene and paclitaxel could be used as a therapeutic strategy by which to overcome ovarian cancer.

Keywords: bazedoxifene; epithelial‑mesenchymal transition; interleukin‑6; ovarian cancer; paclitaxel; signal transducer and activator of transcription 3; signalling pathway.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cytokine Receptor gp130 / drug effects*
  • Drug Therapy, Combination
  • Epithelial-Mesenchymal Transition / drug effects*
  • Female
  • Glycoproteins / drug effects
  • Humans
  • Indoles / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Ovarian Neoplasms / drug therapy*
  • Paclitaxel / pharmacology*
  • STAT3 Transcription Factor / drug effects*
  • Selective Estrogen Receptor Modulators / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • Glycoproteins
  • Il6st protein, mouse
  • Indoles
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Selective Estrogen Receptor Modulators
  • Stat3 protein, mouse
  • glycoprotein 130, human
  • Cytokine Receptor gp130
  • Paclitaxel
  • bazedoxifene

Grant support

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (grant nos. NRF-2018R1D1A1B07049780, 2018R1A6A1A03025108, 2021R1A2C2009782 and 2021R1A6A3A1303840811).