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

Abstract

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.

Figure 1. The synthesis and processing of PrP from pre-pro-PrP to pro-PrP to mature, glycosylated, GPI-anchored PrP

GPI: Glycosylphosphatidylinositol; LPS: Leader peptide signal sequence; N: N-linked glycans; PrP: Prion protein; PSS: Peptide signal sequence; S–S: Disulfide bridge; TM: Putative transmembrane domain.

Figure 2. Dimeric filamin A

At the N-terminus of each monomeric unit, there is an actin-binding domain, followed by 24 β-sheet Ig-like domain. Domain 24 is the self-association domain. The two hinge regions provide flexibility to permit high-angle binding of the F-actin filament.

Figure 3. Cell surface pro-PrP and normal, glycosyated, GPI-anchored PrP

Cell surface pro-PrP is using the GPI-PSS as a transmembrane domain. The GPI-PSS transverses the membrane and interacts with FLNa. The ABD of FLNa binds actin filaments. The normal PrP is GPI-anchored and glycosylated. ABD: Actin-binding domain; GPI: Glycosylphosphatidylinositol; PrP: Prion protein; PSS: Peptide signal sequence.

Figure 4. Inhibition of hepatocarcinoma cell migration with the KKRPK-PrP-GPI-PSS synthetic peptide

Various concentrations of the synthetic peptide were added at the beginning of the wound-healing assay. At 24 h after the assay, the areas of the wound were imaged on a microscope equipped with a digital camera system, and quantified. Inhibition of cell migration was determined by comparing the healed area of nontreated cells with the healed area of cells treated either with the KKRPK-PrP-GPI-PSS peptide or the KKRPK-control peptide. GPI: Glycosylphosphatidylinositol; PrP: Prion protein; PSS: Peptide signal sequence.