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.
Pancreatic ductal adenocarcinoma is one of the most lethal cancers. The Hippo pathway is involved in tumorigenesis and remodeling of tumor microenvironments. Hypoxia exists in the microenvironment of solid tumors, including pancreatic ductal adenocarcinoma and plays a vital role in tumor progression and metastasis. However, it remains unclear how hypoxia interacts with the Hippo pathway to regulate these events. In this study, expressions of yes-associated protein 1 and hypoxia-inducible factor-1α were found to be elevated in pancreatic ductal adenocarcinoma samples compared with those in matched adjacent non-tumor samples. Moreover, hypoxia-inducible factor-1α expression was positively correlated with yes-associated protein 1 level in pancreatic ductal adenocarcinoma tissues. The higher expression of nuclear yes-associated protein 1 was associated with poor histological grade and prognosis for pancreatic ductal adenocarcinoma patients. In vitro, yes-associated protein 1 was highly expressed in pancreatic ductal adenocarcinoma cells. Depletion of yes-associated protein 1 inhibited the invasion of pancreatic ductal adenocarcinoma cells via downregulation of Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-13, and upregulation of E-cadherin. In addition, hypoxia promoted the invasion of pancreatic ductal adenocarcinoma cells via regulating the targeted genes. Hypoxia also deactivated the Hippo pathway and induced yes-associated protein 1 nuclear translocation. Furthermore, depletion of yes-associated protein 1 or hypoxia-inducible factor-1α suppressed the invasion of pancreatic ductal adenocarcinoma cells under hypoxia. Mechanism studies showed that nuclear yes-associated protein 1 interacted with hypoxia-inducible factor-1α and activated Snail transcription to participate in epithelial-mesenchymal transition-mediated and matrix metalloproteinase-mediated remodeling of tumor microenvironments. Collectively, yes-associated protein 1 is an independent prognostic predictor that interacts with hypoxia-inducible factor-1α to enhance the invasion of pancreatic cancer cells and remodeling of tumor microenvironments. Therefore, yes-associated protein 1 may serve as a novel promising target to enhance therapeutic effects for treating pancreatic cancer.
Abstract. Sorafenib is a type of multikinase inhibitor that exhibits antiangiogenic and antiproliferative effects; in addition, sorafenib is a unique first-line drug recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, the effectiveness of HCC treatment remains poor due to acquired drug resistance. It has been suggested that hypoxia, induced as a results of the antiangiogenic effects of sustained sorafenib treatment, may be an important factor in sorafenib resistance. The transcription factor hypoxia-inducible factor (HIF)-2α has been reported to be associated with cell proliferation under hypoxic conditions; therefore, it was hypothesized that hypoxia may enhance tumor cell proliferation via this mechanism. The present study aimed to evaluate whether the knock-down of HIF-2α was able to enhance the therapeutic efficacy of sorafenib in order to effectively treat HCC. The results demonstrated that hypoxia protected HCC cells against sorafenib; however, short hairpin RNA-HIF-2α transfection in combination with sorafenib treatment exhibited a significantly synergistic effect against HCC cell proliferation. In addition, HCC cells acquired increased β-catenin/C-Myc expression, which enhanced proliferation under hypoxic conditions; however, targeted knock-down of HIF-2α or C-Myc markedly decreased cell proliferation in HCC cells. In conclusion, the results of the present study indicated that the targeted knock-down of HIF-2α in combination with sorafenib may be a promising strategy for the treatment of HCC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.