Journal Article

Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP‐TEAD complex

Zhong, Jingtao, Wang, Fuhai, Li, Tao, Li, Jie, Wei, Honglong, Sun, Xueying, Wang, Yong, Xiu, Peng

2017

Overview

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. The Yes‐associated protein‐1 (YAP) plays a critical role in cell proliferation, apoptosis and angiogenesis. Verteporfin is a photosensitizer used in photodynamic therapy and also a small molecular inhibitor of the Hippo‐YAP pathway. However, little is known about whether verteporfin could inhibit YAP activity in PDAC cells. Our present results showed that verteporfin suppressed the proliferation of human PDAC PANC‐1 and SW1990 cells by arresting cells at the G1 phase, and inducing apoptosis in dose‐ and time‐dependent manners. Verteporfin also inhibited the tumor growth on the PDAC xenograft model. Treatment with verteporfin led to downregulation of cyclinD1 and cyclinE1, modulation of Bcl‐2 family proteins and activation of PARP. In addition, verteporfin exhibited an inhibitory effect on angiogenesis and vasculogenic mimicry via suppressing Ang2, MMP2, VE‐cadherin, and α‐SMA expression in vitro and in vivo. Mechanism studies demonstrated that verteporfin impaired YAP and TEAD interaction to suppress the expression of targeted genes. Our results provide a foundation for repurposing verteporfin as a promising anti‐tumor drug in the treatment of pancreatic cancer by targeting the Hippo pathway. Verteporfin suppresses cell survival, migration, angiogenesis and vasculogenic mimicry of pancreatic cancer via disrupting the YAP‐TEAD interaction. Verteporfin inhibits cell cycle progression by suppressing cyclinD1 and cyclinE1 expression. Verteporfin induces cell apoptosis by activating the intrinsic apoptosis pathway. Verteporfin also inhibits Ang2, MMP2, VE‐cadherin and α‐SMA expression to suppress angiogenesis and vasculogenic mimicry.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adaptor Proteins, Signal Transducing - antagonists & inhibitors / Adaptor Proteins, Signal Transducing - metabolism / Adenocarcinoma / Angiogenesis / Animals / Antigens, CD / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Cadherins / Cadherins - antagonists & inhibitors / Cancer therapies / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - pathology / Cell adhesion & migration / Cell cycle / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cell survival / Cell Survival - drug effects / Cyclin D1 - metabolism / Cyclin E - metabolism / DNA-Binding Proteins - antagonists & inhibitors / DNA-Binding Proteins - metabolism / G1 phase / G1 Phase Cell Cycle Checkpoints - drug effects / Gelatinase A / Gene expression / Human Umbilical Vein Endothelial Cells / Humans / Hypoxia / Macular degeneration / Male / Matrix Metalloproteinase 2 - metabolism / Medical prognosis / Metastasis / Mice / Mice, Inbred BALB C / Mice, Nude / Microscopy / Mimicry / Neovascularization, Pathologic - drug therapy / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - metabolism / Oncogene Proteins - metabolism / Original / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - pathology / Phosphoproteins - antagonists & inhibitors / Phosphoproteins - metabolism / Photodynamic therapy / Poly (ADP-Ribose) Polymerase-1 - metabolism / Poly(ADP-ribose) polymerase / Porphyrins - pharmacology / Proto-Oncogene Proteins c-bcl-2 - metabolism / Stem cells / TEA Domain Transcription Factors / Transcription Factors - antagonists & inhibitors / Transcription Factors - metabolism / Tumors / vasculogenic mimicry / Verteporfin / Vesicular Transport Proteins - antagonists & inhibitors / Xenograft Model Antitumor Assays / Xenografts / YAP-Signaling Proteins / Yes-associated protein