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

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.