title: Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein.
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.
authors: Gray Institute of Radiation Oncology and Biology, Medical Science Division, University of Oxford, Oxford, United Kingdom.
authors: Chad M
authors: CM
authors: McKee
authors: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
authors: Yunchuan
authors: Y
authors: Ding
authors: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
authors: Jianfeng
authors: J
authors: Zhou
authors: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
authors: Chunrui
authors: C
authors: Li
authors: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
authors: Liang
authors: L
authors: Huang
authors: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
authors: Xiangke
authors: X
authors: Xin
authors: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
authors: Jing
authors: J
authors: He
authors: Penn State Hershey Cancer Institute, Penn State University, Hershey, PA, USA.
authors: Joshua E
authors: JE
authors: Allen
authors: Penn State Hershey Cancer Institute, Penn State University, Hershey, PA, USA.
authors: Wafik S
authors: WS
authors: El-Deiry
authors: Gray Institute of Radiation Oncology and Biology, Medical Science Division, University of Oxford, Oxford, United Kingdom.
authors: Yunhong
authors: Y
authors: Cao
authors: Gray Institute of Radiation Oncology and Biology, Medical Science Division, University of Oxford, Oxford, United Kingdom.
authors: Ruth J
authors: RJ
authors: Muschel
authors: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
authors: Danmei
authors: D
authors: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D058258:Serpin E2 / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D058258:Serpin E2; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D014568:Urokinase-Type Plasminogen Activator