PUBLICATION
The Fibrillin-1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells
- Authors
- Wang, Z., Chen, W., Zuo, L., Xu, M., Wu, Y., Huang, J., Zhang, X., Li, Y., Wang, J., Chen, J., Wang, H., Sun, H.
- ID
- ZDB-PUB-220303-25
- Date
- 2022
- Source
- Cancer communications (London, England) 42(3): 245-265 (Journal)
- Registered Authors
- Wang, Jing
- Keywords
- Fibrillin-1, STAT2, VEGFR, angiogenesis, chemoresistance, glycolysis, organoid, ovarian cancer
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Cisplatin/pharmacology
- Drug Resistance, Neoplasm
- Female
- Fibrillin-1/genetics
- Fibrillin-1/metabolism
- Glycolysis
- Humans
- Mice
- Mice, Knockout
- Mice, Nude
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism
- Organoids/metabolism
- Ovarian Neoplasms*/drug therapy
- Ovarian Neoplasms*/genetics
- STAT2 Transcription Factor/metabolism
- Vascular Endothelial Growth Factor A/metabolism
- Vascular Endothelial Growth Factor A/therapeutic use
- Vascular Endothelial Growth Factor Receptor-2*/genetics
- Vascular Endothelial Growth Factor Receptor-2*/metabolism
- Vascular Endothelial Growth Factor Receptor-2*/therapeutic use
- Zebrafish/metabolism
- PubMed
- 35234370 Full text @ Cancer Commun (Lond)
Citation
Wang, Z., Chen, W., Zuo, L., Xu, M., Wu, Y., Huang, J., Zhang, X., Li, Y., Wang, J., Chen, J., Wang, H., Sun, H. (2022) The Fibrillin-1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells. Cancer communications (London, England). 42(3):245-265.
Abstract
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 (chemoresistant 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 FBN1-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 Fӧrster 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 ovarian cancer organoids and tissues, indicating that FBN1 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 treatment 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 Tyr1054 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), promoted 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 chemoresistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis. The present study suggested a novel FBN1-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping