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Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414153/ https://www.ncbi.nlm.nih.gov/pubmed/25686839 |
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author | McKee, Chad M. Ding, Yunchuan Zhou, Jianfeng Li, Chunrui Huang, Liang Xin, Xiangke He, Jing Allen, Joshua E. El-Deiry, Wafik S. Cao, Yunhong Muschel, Ruth J. Xu, Danmei |
author_facet | McKee, Chad M. Ding, Yunchuan Zhou, Jianfeng Li, Chunrui Huang, Liang Xin, Xiangke He, Jing Allen, Joshua E. El-Deiry, Wafik S. Cao, Yunhong Muschel, Ruth J. Xu, Danmei |
author_sort | McKee, Chad M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4414153 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-44141532015-05-08 Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein McKee, Chad M. Ding, Yunchuan Zhou, Jianfeng Li, Chunrui Huang, Liang Xin, Xiangke He, Jing Allen, Joshua E. El-Deiry, Wafik S. Cao, Yunhong Muschel, Ruth J. Xu, Danmei Oncotarget Research Paper 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. Impact Journals LLC 2015-02-17 /pmc/articles/PMC4414153/ /pubmed/25686839 Text en Copyright: © 2015 McKee et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper McKee, Chad M. Ding, Yunchuan Zhou, Jianfeng Li, Chunrui Huang, Liang Xin, Xiangke He, Jing Allen, Joshua E. El-Deiry, Wafik S. Cao, Yunhong Muschel, Ruth J. Xu, Danmei Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein |
title | Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein |
title_full | Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein |
title_fullStr | Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein |
title_full_unstemmed | Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein |
title_short | Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein |
title_sort | protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of x-chromosome-linked inhibitor of apoptosis protein |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414153/ https://www.ncbi.nlm.nih.gov/pubmed/25686839 |
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