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

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 VEGFR3 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 dosedependent 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.

Automated summary

In this study, the researchers investigated the pathological role of VEGFR-3 and the effects of SAR131675 in ovarian cancer cells. The results showed that SAR131675 effectively inhibited VEGFR-3/ERK1/2/AKT pathway, leading to the suppression of proliferation and migration, as well as the promotion of cell cycle arrest and apoptosis in ovarian cancer cells.