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

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...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Biology Source Type: research