Abstract
Protease nexin 1 (PN1) is an endogenous serine protease inhibitor (SERPIN), expressed at high levels in the prostate, and capable of inhibiting the proliferation of prostate cancer cells. We previously showed that PN1-uPA complexes inhibited Sonic Hedgehog (SHH) signalling through engagement of the LRP receptor. Here, we describe an alternative anti-proliferative mechanism through which PN1 expression leads to apoptosis. In prostate cancer cells, increased expression of PN1 led to substantial reduction of XIAP levels and apoptosis mediated through the uPAR, but not the LRP receptor. The alterations in XIAP were effected in two ways 1) via alteration in the NF-κB pathway, a pathway known to signal XIAP transcription and 2) by promoting XIAP instability. The AKT pathway is known to phosphorylate XIAP at serine 87 leading to protein stability and PN1 expression is shown to interfere with this process. As a result of both mechanisms, programmed cell death is substantially increased. Consistent with these observations, reduced PN1 protein correlated with elevated p65/XIAP expression and with higher Gleason scores in human prostate tissue arrays. Thus, PN1 expression appears to differentially down-regulate distinct oncogenic pathways depending upon the cell surface receptor engaged by its complexes and demonstrates a novel molecular mechanism by which the protein can promote tumor cell apoptosis.
Highlights
A distinctive feature of tumor growth is uncontrolled cell proliferation that largely bypasses the process of programmed cell death, or apoptosis [1]
We have found that protease nexin-1 (PN1)-mediated inhibition of urokinase plasminogen activator (uPA) and its signalling through the uPA receptor, but not lipoprotein receptorrelated protein-1 (LRP-1), results in a downstream cascade of events leading to a cellular reduction in XIAP
Increased cell death occurs in xenografts formed after innoculation with recombinant PN1 in the Matrigel compared to controls (Sup. 1C)
Summary
A distinctive feature of tumor growth is uncontrolled cell proliferation that largely bypasses the process of programmed cell death, or apoptosis [1]. XIAP (X-chromosome-linked inhibitor of apoptosis protein) is a cellular factor that plays a central role in regulating cell death pathways [4]. XIAP is a member of the inhibitor of apoptosis (IAP) family of proteins that target caspases, the effector molecules of cell death [9]. XIAP is one of eight individual members of the IAP family, but is the www.impactjournals.com/oncotarget most potent inhibitor as determined by strength of binding to its caspase targets [9]. Many small molecules or antisense nucleotides have been designed to block XIAP and engage the cell death program [5, 16,17,18], with varying success. We show evidence that an endogenous serine protease inhibitor, protease nexin-1 (PN1), leads to reduced expression of XIAP, resulting in induction of apoptosis in prostate cancer
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