The Fibrillin-1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.Methods:RNA sequencing of cisplatin-resistant and sensitive(chemoresis-tant and chemosensitive,respectively)ovarian cancer organoids was performed,followed by detection of the expression level of fibrillin-1(FBN1)in organoids and clinical specimens of ovarian cancer.Subsequently,glucose metabolism,angiogenesis,and chemosensitivity were analyzed in structural glycoprotein FBNl-knockout cisplatin-resistant ovarian cancer organoids and cell lines.To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer,immunoprecipitation,silver nitrate staining,mass spectrometry,immunofluorescence,Western blotting,and Forister resonance energy transfer-fluorescence lifetime imaging analyses were performed,followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.Results:FBN1 expression was significantly enhanced in cisplatin-resistant ovar-ian cancer organoids and tissues,indicating that FBNI might be a key factor in chemoresistance of ovarian cancer.We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo,which promoted the cisplatin-resistance of ovarian cancer.Knockout of FBN1 combined with treat-ment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells.Mechanistically,FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2)at the Tyrl054 residue,which activated its downstream focal adhesion kinase(FAK)/protein kinase B(PKB or AKT)pathway,induced the phosphorylation of signal transducer and activator of transcription 2(STAT2)at the tyrosine residue 690(Tyr690),pro-moted the nuclear translocation of STAT2,and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.Conclusions:The FBN1/VEGFR2/STAT2 signaling axis may induce chemore-sistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis.The present study suggested a novel FBNl-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.

Programmed death ligand-1 regulates angiogenesis and metastasis by participating in the c-JUN/VEGFR2 signaling axis in ovarian cancer

Background:Although programmed cell death-ligand 1(PD-L1)plays a wellknown function in immune checkpoint response by interacting with programmed cell death-1(PD-1),the cell-intrinsic role of PD-L1 in tumors is still unclear.Here,we explored the molecular regulatory mechanism of PD-L1 in the progression and metastasis of ovarian cancer.Methods:Immunohistochemistry of benign tissues and ovarian cancer samples was performed,followed by migration,invasion,and angiogenesis assays in PDL1-knockdown ovarian cancer cells.Immunoprecipitation,mass spectrometry,and chromatin immunoprecipitation were conducted along with zebrafish and mouse experiments to explore the specific functions and mechanisms of PD-L1 in ovarian cancer.Results:Our results showed that PD-L1 induced angiogenesis,which further promoted cell migration and invasion in vitro and in vivo of ovarian cancer.Mechanistically,PD-L1 was identified to directly interact with vascular endothelial growth factor receptor-2(VEGFR2)and then activated the FAK/AKT pathway,which further induced angiogenesis and tumor progression,leading to poor prognosis of ovarian cancer patients.Meanwhile,PD-L1 was found to be regulated by the oncogenic transcription factor c-JUN at the transcriptional level,which enhanced the expression of PD-L1 in ovarian cancer.Furthermore,we demonstrated that PD-L1 inhibitor durvalumab,combined with the antiangiogenic drug,apatinib,could enhance the effect of anti-angiogenesis and the inhibition of cell migration and invasion.Conclusion:Our results demonstrated that PD-L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c-JUN/VEGFR2 signaling axis,suggesting that the combination of PD-L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients.