Protease nexin 1: A novel inducer of prostate tumor cell apoptosis

Yunchuan Ding, C. Mckee, R. Muschel, Danmei Xu
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Abstract

Protease nexin 1 (PN1), a member of serine protease inhibitors (SERPINs) family, is known for its ability to bind and inhibit a wide range of proteases. Recently, we have found that PN1 is able to induce prostate cancer cell undergoing apoptosis through a distinct mechanism of engaging uPA-uPAR complexes and the regulation of two independent downstream signaling cascades, leading to the repression of X-linked inhibitor of apoptosis protein (XIAP). In this process, PN1 expression reduces the expression of NF-κB signalling component p65 and thereby lessens xiap transcription. Alternately, PN1 activity can prevent the stability of XIAP by reducing XIAP phosphorylation at serine 87 via a blockade of AKT signaling. A combination of exogenous PN1 and TRAIL leads to a substantial growth lag in prostate cancer xenografts, indicating the potential of PN1 as a promising target for improving prostate cancer therapy. Furthermore, human prostate tissue arrays show inverse levels of PN1 and XIAP in tumor and normal prostate. Hence, the PN1-uPA regulatory axis may serve as an inducer of tumor cell apoptosis by modulating survival pathways, and therefore delay the tumor growth of prostate cancer.
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蛋白酶连接蛋白1:一种新的前列腺肿瘤细胞凋亡诱导因子
蛋白酶连接蛋白1 (PN1)是丝氨酸蛋白酶抑制剂(SERPINs)家族的一员,以其结合和抑制多种蛋白酶的能力而闻名。最近,我们发现PN1能够通过参与uPA-uPAR复合物和调节两个独立的下游信号级联的独特机制诱导前列腺癌细胞发生凋亡,导致X-linked inhibitor of apoptosis protein (XIAP)的抑制。在这个过程中,PN1的表达降低了NF-κB信号元件p65的表达,从而减少了xiap的转录。另外,PN1活性可以通过阻断AKT信号通路,降低XIAP丝氨酸87的磷酸化,从而阻止XIAP的稳定性。外源性PN1和TRAIL的结合导致前列腺癌异种移植物的生长明显滞后,这表明PN1可能是改善前列腺癌治疗的一个有希望的靶点。此外,人类前列腺组织阵列显示PN1和XIAP在肿瘤和正常前列腺中呈反比水平。因此,PN1-uPA调控轴可能通过调节生存通路,作为肿瘤细胞凋亡的诱导剂,从而延缓前列腺癌肿瘤的生长。
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