title: p53-induced gene 3 mediates cell death induced by glutathione peroxidase 3.
abstract: Expression of glutathione peroxidase 3 (GPx3) is down-regulated in a variety of human malignancies. Both methylation and deletion of GPx3 gene underlie the alterations of GPx3 expression in prostate cancer. A strong correlation between the down-regulation of GPx3 expression and progression of prostate cancer and the suppression of prostate cancer xenografts in SCID mice by forced expression of GPx3 suggests a tumor suppression role of GPx3 in prostate cancer. However, the mechanism of GPx3-mediated tumor suppression remains unclear. In this report, GPx3 was found to interact directly with p53-induced gene 3 (PIG3). Forced overexpression of GPx3 in prostate cancer cell lines DU145 and PC3 as well as immortalized prostate epithelial cells RWPE-1 increased apoptotic cell death. Expression of GPx3(x73c), a peroxidase-negative OPAL codon mutant, in DU145 and PC3 cells also increased cell death. The induced expression of GPx3 in DU145 and PC3 cells resulted in an increase in reactive oxygen species and caspase-3 activity. These activities were abrogated by either knocking down PIG3 or mutating the PIG3 binding motif in GPx3 or binding interference from a peptide corresponding to PIG3 binding motif in GPx3. In addition, UV-treated RWPE-1 cells underwent apoptotic death, which was partially prevented by knocking down GPx3 or PIG3, suggesting that GPx3-PIG3 signaling is critical for UV-induced apoptosis. Taken together, these results reveal a novel signaling pathway of GPx3-PIG3 in the regulation of cell death in prostate cancer.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Katherine
authors.initials: K
authors.lastname: Luo
authors.forename: Lang-Zhu
authors.initials: LZ
authors.lastname: Tan
authors.forename: Bao-Guo
authors.initials: BG
authors.lastname: Ren
authors.forename: Li-Qun
authors.initials: LQ
authors.lastname: Gu
authors.forename: George
authors.initials: G
authors.lastname: Michalopoulos
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Luo
authors.forename: Yan P
authors.initials: YP
authors.lastname: Yu
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; C411296:TP53I3 protein, human; D016159:Tumor Suppressor Protein p53; C486484:GPX3 protein, human; D005979:Glutathione Peroxidase