SAR131675 exhibits anticancer activity on human ovarian cancer cells through inhibition of VEGFR-3/ERK1/2/AKT signaling pathway

Zeinab Babaei; Mojtaba Panjehpour; Hadi Parsian; Mahmoud Aghaei

doi:10.1016/j.cellsig.2023.110856

SAR131675 exhibits anticancer activity on human ovarian cancer cells through inhibition of VEGFR-3/ERK1/2/AKT signaling pathway

Cell Signal. 2023 Nov:111:110856. doi: 10.1016/j.cellsig.2023.110856. Epub 2023 Aug 19.

Authors

Zeinab Babaei¹, Mojtaba Panjehpour², Hadi Parsian³, Mahmoud Aghaei⁴

Affiliations

¹ Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Clinical Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
² Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
³ Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
⁴ Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: maghaei@pharm.mui.ac.ir.

PMID: 37598918
DOI: 10.1016/j.cellsig.2023.110856

Abstract

Vascular endothelial growth factor receptor-3 (VEGFR-3) is known to participate in tumorigenesis and lymphangiogenesis, and as such, has the potential to serve as a molecular target for cancer therapy. SAR131675 is a highly selective VEGFR-3 antagonist that has an inhibitive effect on lymphatic cell growth. However, the anticancer effects and underlying mechanisms of SAR131675 in ovarian cancer remain poorly understood. In this study, we investigated the pathological role of VEGFR-3, and the effects of SAR131675 on proliferation, cell cycle, migration, and apoptosis in ovarian cancer cells. Our results showed that the mRNA and protein of VEGFR-3 were expressed in OVCAR3 and SKOV3 ovarian cancer cells, and this receptor was activated following stimulation with 50 ng/ml VEGF-C Cys156Ser (VEGF-CS), a selective ligand for VEGFR-3. Enhancing VEGFR-3 phosphorylation by treatment of ovarian cancer cells with VEGF-CS resulted in increased levels of phosphorylated extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT. Moreover, our data demonstrated that SAR131675 inhibited VEGF-CS-mediated proliferation, colony formation, and migration of cancer cells in a dose-dependent manner. In addition, inhibition of VEGFR-3 activation with SAR131675 significantly increased cell cycle arrest and promoted apoptosis in both OVCAR3 and SKOV3 cells. Mechanistically, SAR131675 effectively suppressed the VEGF-CS-induced phosphorylation of VEGFR-3 and its downstream effectors including activated ERK1/2 and AKT in ovarian cancer cells. Our results reveal an anticancer activity of SAR131675 on the growth and migration of ovarian cancer cells, which may be through inhibiting VEGFR-3/ERK1/2/AKT pathway. SAR131675 may serve as an effective targeted drug for ovarian cancer.

Keywords: AKT; Anticancer activity; ERK1/2; Ovarian cancer; SAR131675; Vascular endothelial growth factor receptor-3.