YAP inhibitor verteporfin suppresses tumor angiogenesis and overcomes chemoresistance in esophageal squamous cell carcinoma

Purpose: Targeting angiogenesis is an attractive strategy for the effective treatment of Cancer. This study aimed to investigate the anti-cancer activities of YAP Inhibitor verteporfin (VP) in esophageal squamous cell carcinoma (ESCC) cells through its inhibitory effect on tumor angiogenesis.

Methods: Cell proliferation, Apoptosis, migration and invasion abilities were estimated by MTT, colony formation, DAPI staining, wound healing and transwell assays, respectively. Human umbilical vein endothelial cell (HUVEC) tube formation assay and chick embryo chorioallantoic membrane (CAM) model were used to observe angiogenesis in vitro and in vivo. The interactions between ESCC cells and HUVECs were assessed by cell chemotactic migration and adhesion assays. The expression levels of angiogenesis-related molecules were detected by Western blot.

Results: We found that VP was potential to inhibit ESCC cell proliferation, migration, invasion and induce Apoptosis in the dose-dependent fashion. VP also significantly suppressed proliferation, migration, and tube formation of HUVECs and promoted Apoptosis of HUVECs, and reduced angiogenesis in CAM. Moreover, VP inhibited ESCC cell-induced angiogenesis in vitro by decreasing HUVEC chemotactic migration, adhesion and tube formation, and also reduced ESCC cell-induced neovascularization of the CAM in vivo. In addition, VP suppressed the expression of pro-angiogenic molecules such as VEGFA, MMP-2 and β-catenin in ESCC cells. Furtherly, VP increased the chemosensitivity of ESCC-resistant cells to paclitaxel (PTX). The combination of VP and PTX attenuated the resistant cell-mediated angiogenesis in vitro and in vivo.

Conclusion: These results reveal for the first time that VP potently inhibits malignant progression and overcomes chemoresistance of ESCC cells via inhibition of tumor angiogenesis. It provides insight into a new strategy for the treatment of ESCC that VP could be a potential drug candidate for targeting tumor angiogenesis.

Chemoresistance; Esophageal squamous cell carcinoma; Tumor angiogenesis; Verteporfin.