Anlotinib inhibits synovial sarcoma by targeting GINS1: a novel downstream target oncogene in progression of synovial sarcoma

Clin Transl Oncol. 2019 Dec;21(12):1624-1633. doi: 10.1007/s12094-019-02090-2. Epub 2019 Apr 8.

Abstract

Background: Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma with a poor prognosis owing to its resistance to radiation and chemotherapy. Thus, novel therapeutic strategies for SS are urgently required. Anlotinib, a new oral tyrosine kinase inhibitor, is designed to primarily inhibit multi-targets in vasculogenesis and angiogenesis. This study was designed to characterize its antitumor efficacy and possible mechanism in patients with advanced refractory synovial sarcoma.

Methods: Anlotinib's antitumor effect was evaluated in vivo and vitro. Downstream targets of anlotinib in treating synovial sarcoma were analyzed through microarray assay. Cell proliferation and apoptosis analyses were performed to evaluate the impact of candidate downstream gene depletion in synovial sarcoma cells. Microarray assay were carried out to investigate potential signal network related with candidate downstream gene.

Results: Anlotinib significantly suppresses synovial sarcoma proliferation in PDTX model and cell lines. Additionally, GINS1 (also named as PSF1, Partner of SLD Five 1), rather than other conventional gene target, was demonstrated to be a vital target of anlotinib's antitumor effect in synovial sarcoma through microarray assay. Expression of GINS1 was remarkably higher in synovial sarcoma tumor samples and related with poor outcome. Knockdown of GINS1 expression could remarkably inhibit proliferation and promote apoptosis in vitro. Meanwhile, through microarray assay, CITED2, EGR1, SGK1 and SPP1 were identified and further validated by qPCR/WB as downstream targets of GINS1.

Conclusion: Anlotinib might suppress proliferation of SS through a novel downstream GINS1-regulated network which plays a vital function in SS proliferation and also demonstrated that targeting the GINS1-regulated signal pathway could be a potential strategy for management of SS.

Keywords: Anlotinib; Apoptosis; GINS1; Proliferation; Synovial sarcoma.

MeSH terms

  • Apoptosis / drug effects
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / genetics
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / drug effects*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Early Growth Response Protein 1 / drug effects
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Immediate-Early Proteins / drug effects
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Indoles / therapeutic use*
  • Neoplasm Proteins / drug effects*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Osteopontin / drug effects
  • Osteopontin / genetics
  • Osteopontin / metabolism
  • Protein Array Analysis
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Serine-Threonine Kinases / drug effects
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Quinolines / therapeutic use*
  • RNA, Messenger / analysis
  • Repressor Proteins / drug effects
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Sarcoma, Synovial / drug therapy*
  • Sarcoma, Synovial / genetics
  • Trans-Activators / drug effects
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • CITED2 protein, human
  • DNA-Binding Proteins
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • GINS1 protein, human
  • Immediate-Early Proteins
  • Indoles
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Quinolines
  • RNA, Messenger
  • Repressor Proteins
  • SPP1 protein, human
  • Trans-Activators
  • anlotinib
  • Osteopontin
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase