title: Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1.
abstract: Up-regulation of human prion protein (PrP) in patients with pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. However, the underlying molecular mechanism of PrP-mediated tumorigenesis is not completely understood. In this study, we found that PDAC cell lines can be divided into either PrP high expresser or PrP low expresser. In addition to filamin A (FLNA), PrP interacts with Notch1, forming a PrP/FLNA/Notch1 complex. Silencing PrP in high-expresser cells decreases Notch1 expression and Notch1 signaling. These cells exhibited decreased proliferation, xenograft growth, and tumor invasion but show increased tumor apoptosis. These phenotypes were rescued by ectopically expressed and activated Notch1. By contrast, overexpression of PrP in low expressers increases Notch1 expression and signaling, enhances proliferation, and increases tumor invasion and xenograft growth that can be blocked by a Notch inhibitor. Our data further suggest that PrP increases Notch1 stability likely through suppression of Notch proteosome degradation. Additionally, we found that targeting PrP combined with anti-Notch is much more effective than singularly targeted therapy in retarding PDAC growth. Finally, we show that coexpression of PrP and Notch1 confers an even poorer prognosis than PrP expression alone. Taken together, our results have unraveled a novel molecular pathway driven by interactions between PrP and Notch1 in the progression of PDAC, supporting a critical tumor-promoting role of Notch1 in PrP-expressing PDAC tumors.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Shuiliang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Huankai
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Pathology, Affiliated Zhongda Hospital, Southeast University, Nanjing, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Weihuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Neetha
authors.initials: N
authors.lastname: Parameswaran
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Mark
authors.initials: M
authors.lastname: Jackson
authors.affiliation: Molecular & Cellular Biology Program, University of Massachusetts, Amherst, Massachusetts.
authors.forename: Barbara
authors.initials: B
authors.lastname: Osborne
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bedogni
authors.affiliation: State Key Laboratory of Virology and Department of Molecular Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Man-Sun
authors.initials: MS
authors.lastname: Sy
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio. Electronic address: lan.zhou@case.edu.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival; D018450:Disease Progression; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D000072002:Prion Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D000072002:Prion Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1