title: Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP-TEAD complex.
abstract: 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.
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Honglong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiu
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015820:Cadherins / Q000037:antagonists & inhibitors; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D011166:Porphyrins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077362:Verteporfin; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins; D000099152:Cadherin 5
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000970:Antineoplastic Agents; D015820:Cadherins; D019938:Cyclin D1; D019927:Cyclin E; D004268:DNA-Binding Proteins; D020778:Matrix Metalloproteinase 2; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010750:Phosphoproteins; D000071137:Poly (ADP-Ribose) Polymerase-1; D011166:Porphyrins; D019253:Proto-Oncogene Proteins c-bcl-2; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors; D000077362:Verteporfin; D033921:Vesicular Transport Proteins; D000091102:YAP-Signaling Proteins; D000099152:Cadherin 5; C530104:CCND1 protein, human; C475820:CCNE1 protein, human; C057182:TEAD1 protein, human; C555023:VPS51 protein, human; C088374:YAP1 protein, human; C499320:PARP1 protein, human; C522361:MMP2 protein, human
keywords: Angiogenesis; apoptosis; pancreatic cancer; vasculogenic mimicry; verteporfin