Caulerpin suppresses tumor-associated angiogenesis and tumor growth via Hippo signaling in cervical cancer

Caulerpin, a bisindole alkaloid derived from green algae of the genus Caulerpa, has exhibited a promising anti-proliferative effect on various tumor cells in vitro. However, its pharmacological potential has not been intensively explored in cervical cancer. In this study, the antitumor property of caulerpin was assessed in cervical cancer cells (HeLa and SiHa cells) and xenograft mouse models. It was found that caulerpin significantly inhibited cell growth, colony formation, migration, invasion and induced cell apoptosis in HeLa and SiHa cells, and inhibited the tumor growth of HeLa xenografts in vivo. In human umbilical vein endothelial cells (HUVECs), caulerpin significantly suppressed proliferation, migration, and tube formation with (indirect) or without (direct effects) tumor-conditioned medium stimulation. Mechanically, caulerpin treatment blocked angiogenesis in vitro and in vivo through suppressing YAP1 nuclear translocation and angiogenesis-related proteins expression, including HIF-1α and VEGFA expression in tumor cells, VEGFR2 and CD31 expression in HUVECs. TDI-011536 (a specific inhibitor of Hippo) effectively reversed the effect of caulerpin. These results demonstrate the anti-angiogenic effect of caulerpin in cervical cancer that Hippo/YAP1 mediates tumor-endothelial cell interaction via VEGF/VEGFR2 signaling, which supports it as a natural product for the management of cervical cancer.