Abstract 2244A: Prion protein cross-talks with Notch1 to promote pancreatic ductal adenocarcinoma progression

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Human prion protein (PrP) is a glycosylphosphatidylino¬sitol (GPI)-anchored membrane protein and has been found to be up-regulated in some of the pancreatic ductal adenocarcinoma (PDAC). Current literature also suggests that over-expression of PrP induces inherent resistance to cancer therapeutics, while repression of PrP induces sensitization to cancer therapeutics. Our previous studies revealed the increased level of PrP expression associated with worse prognosis in PDAC patients. In PDACs, instead of forming normal GPI anchored protein, PrP exists as a pro-prion protein that binds Filamin A (FLNa) and exerts a cascade of activities subsequently augment the invasiveness of PDAC. In this study, we would like to investigate whether PrP also involves other signal transduction pathway in PDACs, especially Notch pathway. Using immunoprecipitation and immunocytometry, we investigated the binding partners for PrP in several PDAC cell lines and found that PrP associates with Notch1 but not with Notch2 or Notch3 in cytoplasm and cell membrane. The association of PrP and Notch1 was further validated by confocal microscopy. Silencing PrP by siRNA not only decreased PrP expression, but also decreased Notch1 in the cytoplasm and the nuclear localized cleaved Notch1. Knocking down PrP in PDAC cells with high levels of PrP led to decreased cell proliferation and tumor invasion and increased apoptosis. PDAC cells showed Increased tumor necrosis after inhibition of PrP in xenografts, which accompanied by down-regulation of intracellular domain of Notch1 (Notch1NTM). In comparison, over-expression of PrP in PDAC cells with lower levels of PrP increased Notch1NTM expression, cell proliferation, tumor invasion, and xenograft tumor growth which could be blocked by the gamma secretase inhibitor. These findings suggest that PrP cross talking Notch1 in PDAC cells regulates pancreatic cancer cell survival and invasion. Elucidating the mechanisms for PrP mediated Notch activation in PDAC will further our long-term goal of understanding the role of oncogenic PrP in conferring pancreatic cancer aggressiveness, and potentially will lead to novel therapeutic options for treatment of pancreatic cancer. Citation Format: Yiwei Wang, Dan Huang, Lan Zhou, Wei Xin. Prion protein cross-talks with Notch1 to promote pancreatic ductal adenocarcinoma progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2244A. doi:10.1158/1538-7445.AM2014-2244A