Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1

Yiwei Wang, Shuiliang Yu, Dan Huang, Min Cui, Huankai Hu, Lihua Zhang, Weihuan Wang, Neetha Parameswaran, Mark Jackson, Barbara Osborne, Barbara Bedogni, Chaoyang Li, Man Sun Sy, Wei Xin, Lan Zhou

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2945-2956
Number of pages12
JournalAmerican Journal of Pathology
Volume186
Issue number11
DOIs
StatePublished - Nov 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1'. Together they form a unique fingerprint.

  • Cite this

    Wang, Y., Yu, S., Huang, D., Cui, M., Hu, H., Zhang, L., Wang, W., Parameswaran, N., Jackson, M., Osborne, B., Bedogni, B., Li, C., Sy, M. S., Xin, W., & Zhou, L. (2016). Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1. American Journal of Pathology, 186(11), 2945-2956. https://doi.org/10.1016/j.ajpath.2016.07.010