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Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma

Kuisheng Liu1,2, Tingting Ren1,2, Yi Huang1,2

  • 1Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.

Cell Death & Disease
|August 25, 2017
PubMed

Insights

Apatinib, a vascular endothelial growth factor receptor-2 inhibitor, shows promise in treating osteosarcoma by inhibiting tumor growth, inducing apoptosis, and regulating autophagy via the VEGFR2/STAT3/BCL-2 pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Osteosarcoma cure rates have stagnated for 30 years, necessitating novel therapeutic strategies.
  • Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) is implicated in osteosarcoma progression, with high levels correlating to poor prognosis.
  • Apatinib, a selective VEGFR2 tyrosine kinase inhibitor, has demonstrated antitumor effects in other cancers but its efficacy in osteosarcoma was unexplored.

Purpose of the Study:

  • To investigate the in vitro and in vivo effects of Apatinib on human osteosarcoma.
  • To elucidate the molecular mechanisms underlying Apatinib's action in osteosarcoma, focusing on the VEGFR2 signaling pathway.
  • To assess the interplay between Apatinib, autophagy, apoptosis, and key signaling molecules like STAT3 and BCL-2.

Main Methods:

  • In vitro studies using osteosarcoma cell lines to assess Apatinib's effects on cell growth, cell cycle, apoptosis, and autophagy.
  • In vivo studies in osteosarcoma models to evaluate Apatinib's therapeutic efficacy.
  • Immunoprecipitation assays to confirm direct binding between VEGFR2 and STAT3.
  • siRNA-mediated knockdown of VEGFR2 and STAT3 to investigate pathway dependencies.
  • Western blotting to analyze protein expression levels (STAT3, BCL-2).

Main Results:

  • Apatinib significantly inhibited osteosarcoma cell growth, induced cell cycle arrest, and promoted apoptosis.
  • Apatinib treatment led to the induction of autophagy, and notably, autophagy inhibition enhanced Apatinib-induced apoptosis.
  • Direct binding between VEGFR2 and STAT3 was confirmed, with STAT3 acting downstream of VEGFR2.
  • Apatinib downregulated both VEGFR2 and STAT3, and further reduced STAT3 and BCL-2 expression.
  • STAT3 knockdown potentiated Apatinib's effects on autophagy and apoptosis, while BCL-2 overexpression attenuated these effects.
  • Apatinib suppressed osteosarcoma growth in vivo.

Conclusions:

  • Apatinib demonstrates significant antitumor activity against osteosarcoma through inhibition of the VEGFR2/STAT3/BCL-2 signaling pathway.
  • The drug effectively suppresses tumor growth, induces apoptosis, and modulates autophagy in osteosarcoma.
  • Targeting the VEGFR2/STAT3/BCL-2 pathway with Apatinib represents a promising therapeutic strategy for osteosarcoma.

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