The fatal attraction between pro-prion and filamin A: Prion as a marker in human cancers

Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA.
Biomarkers in Medicine (Impact Factor: 2.65). 06/2010; 4(3):453-64. DOI: 10.2217/bmm.10.14
Source: PubMed


Pancreatic cancer is the fourth leading cancer causing deaths in the USA, with more than 30,000 deaths per year. The overall median survival for all pancreatic cancer is 6 months and the 5-year survival rate is less than 10%. This dismal outcome reflects the inefficacy of the chemotherapeutic agents, as well as the lack of an early diagnostic marker. A protein known as prion (PrP) is expressed in human pancreatic cancer cell lines. However, in these cell lines, the PrP is incompletely processed and exists as pro-PrP. The pro-PrP binds to a molecule inside the cell, filamin A (FLNa), which is an integrator of cell signaling and mechanics. The binding of pro-PrP to FLNa disrupts the normal functions of FLNa, altering the cell's cytoskeleton and signal transduction machineries. As a result, the tumor cells grow more aggressively. Approximately 40% of patients with pancreatic cancer express PrP in their cancer. These patients have significantly shorter survival compared with patients whose pancreatic cancers lack PrP. Therefore, expression of pro-PrP and its binding to FLNa provide a growth advantage to pancreatic cancers. In this article, we discuss the following points: the biology of PrP, the consequences of binding of pro-PrP to FLNa in pancreatic cancer, the detection of pro-PrP in other cancers, the potential of using pro-PrP as a diagnostic marker, and prevention of the binding between pro-PrP and FLNa as a target for therapeutic intervention in cancers.

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Available from: Man-Sun Sy, Aug 14, 2014
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    • "In pancreatic ductal adenocarcinoma and melanoma, an unglycosylated form of PrP C has been detected, in which the signal sequence for the GPI anchor is thought to span the plasma membrane (Li et al., 2009a) (Fig. 1i). This transmembrane form of PrP binds the cytoskeletal protein, filamin A, which links cell surface receptors to the actin cytoskeleton, and plays important roles in proliferation, survival and cell adhesion (Li et al., 2010; Sy et al., 2010). Interestingly, it has been observed that the PrP signal sequence for the GPI anchor has evolved from a bona fide membrane-spanning sequence (Schmitt-Ulms et al., 2009), which explains it propensity to revert to this phenotype. "
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    ABSTRACT: The cellular prion protein (PrP(C)) is an ubiquitously expressed glycoprotein that is most abundant in the central nervous system. It is thought to play a role in many cellular processes, including neuroprotection, but may also contribute to Alzheimer's disease and some cancers. However, it is best known for its central role in the prion diseases, such as Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), and scrapie. These protein misfolding diseases can be sporadic, acquired, or genetic and are caused by refolding of endogenous PrP(C) into a beta sheet-rich, pathogenic form, PrP(Sc). Once prions are present in the central nervous system, they increase and spread during a long incubation period that is followed by a relatively short clinical disease phase, ending in death. PrP molecules can be broadly categorized as either 'good' (cellular) PrP(C) or 'bad' (scrapie prion-type) PrP(Sc), but both populations are heterogeneous and different forms of PrP(C) may influence various cellular activities. Both PrP(C) and PrP(Sc) are localized predominantly at the cell surface, with the C-terminus attached to the plasma membrane via a glycosyl-phosphatidylinositol (GPI) anchor and both can exist in cleaved forms. PrP(C) also has cytosolic and transmembrane forms, and PrP(Sc) is known to exist in a variety of conformations and aggregation states. Here, we discuss the roles of different PrP isoforms in sickness and in health, and show the subcellular distributions of several forms of PrP that are particularly relevant for PrP(C) to PrP(Sc) conversion and prion-induced pathology in the hippocampus. Copyright © 2015. Published by Elsevier B.V.
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    • "The anti-PrP monoclonal antibody, 8H4, used in the study has been extensively characterized [8] [13] [14]. In normal human pancreas, 8H4 reacts with islet cells but does not react with either ductal cells or acinar cells [7]. Immunohistochemical staining (Mab 8H4, 2.5 µg/ml) was performed in a Leica Bond-III system (Bannockburn , IL). "
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