Binding of pro-prion to filamin A disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer
Binding of pro-prion to filamin A disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer
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DOI：
10.1172/jci39542
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发表时间：
2009-09-01
影响因子：
15.9
通讯作者：
Sy, Man-Sun
中科院分区：
文献类型：
--
作者：
Li, Chaoyang;Yu, Shuiliang;Sy, Man-Sun
细胞朊蛋白（PrP）是一种高度保守、广泛表达的糖基磷脂酰肌醇锚定（GPI锚定）细胞表面糖蛋白。自发现以来，大多数关于PrP的研究都集中在其在神经退行性朊病毒疾病中的作用，而其在神经系统外的功能尚不清楚。在这里，我们报告，人胰腺导管腺癌（PDAC）细胞株表达Prp。然而，PrP既不是糖基化的，也不是GPI锚定的，以pro-PrP存在，并保留其GPI锚肽信号序列（GPI-PSS）。我们还表明，PrP GPI-PSS具有细丝蛋白A结合（FLNa结合）基序，并与FLNa相互作用，FLNa是一种整合细胞力学和信号传导的肌动蛋白相关蛋白。前PrP与FLNa的结合破坏了细胞骨架组织。在PDAC细胞系中通过shRNA抑制PrP表达改变了细胞骨架和多种信号蛋白的表达;它还降低了体外细胞增殖和侵袭力以及体内肿瘤生长。发现患有胰腺癌的人类患者的亚组具有表达pro-PrP的肿瘤。最重要的是，PrP在肿瘤中的表达与患者生存率的显著降低相关。我们认为PrP前体与FLNa的结合扰乱了FLNa的功能，从而促进了PDAC的侵袭性。预防这种相互作用可以为人类PDAC的治疗干预提供有吸引力的靶点。
The cellular prion protein (PrP) is a highly conserved, widely expressed, glycosylphosphatidylinositol-anchored (GPI-anchored) cell surface glycoprotein. Since its discovery, most studies on PrP have focused on its role in neurodegenerative prion diseases, whereas its function outside the nervous system remains unclear. Here, we report that human pancreatic ductal adenocarcinoma (PDAC) cell lines expressed Prp. However, the PrP was neither glycosylated nor GpI-anchored, existing as pro-PrP and retaining its GPI anchor peptide signal sequence (GPI-PSS). We also showed that the PrP GPI-PSS has a filamin A-binding (FLNa-binding) motif and interacted with FLNa, an actin-associated protein that integrates cell mechanics and signaling. Binding of pro-PrP to FLNa disrupted cytoskeletal organization. Inhibition of PrP expression by shRNA in the PDAC cell lines altered the cytoskeleton and expression of multiple signaling proteins; it also reduced cellular proliferation and invasiveness in vitro as well as tumor growth in vivo. A subgroup of human patients with pancreatic cancer was found to have tumors that expressed pro-PrP. Most importantly, PrP expression in tumors correlated with a marked decrease in patient survival. We propose that binding of pro-PrP to FLNa perturbs FLNa function, thus contributing to the aggressiveness of PDAC. Prevention of this interaction could provide an attractive target for therapeutic intervention in human PDAC.