title: Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis.
abstract: Glutathione peroxidase 3 is a selenium-dependent enzyme playing a critical role in detoxifying reactive oxidative species and maintaining the genetic integrity of mammalian cells. In this report, we found that the expression of glutathione peroxidase 3 (GPx3) was widely inactivated in prostate cancers. Complete inactivation of GPx3 correlates with a poor clinical outcome. Deletions (hemizygous and homozygous) of GPx3 gene are frequent in prostate cancer samples, occurring in 39% of the samples studied. The rate of methylation of the GPx3 exon 1 region in prostate cancer samples reaches 90%. Overexpression of GPx3 in prostate cancer cell lines induced the suppression of colony formation and anchorage-independent growth of PC3, LNCaP, and Du145 cells. PC3 cells overexpressing GPx3 reduced invasiveness in Matrigel transmigration analysis by an average of 2.7-fold. Xenografted PC3 cells expressing GPx3 showed reduction in tumor volume by 4.8-fold, elimination of metastasis (0/16 versus 7/16), and reduction of animal death (3/16 versus 16/16). The tumor suppressor activity of GPx3 seems to relate to its ability to suppress the expression of c-met. The present findings suggest that GPx3 is a novel tumor suppressor gene.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Yan P
authors.initials: YP
authors.lastname: Yu
authors.forename: Guoying
authors.initials: G
authors.lastname: Yu
authors.forename: George
authors.initials: G
authors.lastname: Tseng
authors.forename: Kathleen
authors.initials: K
authors.lastname: Cieply
authors.forename: Joel
authors.initials: J
authors.lastname: Nelson
authors.forename: Marie
authors.initials: M
authors.lastname: Defrances
authors.forename: Reza
authors.initials: R
authors.lastname: Zarnegar
authors.forename: George
authors.initials: G
authors.lastname: Michalopoulos
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Luo
mesh_terms: D000818:Animals; D001483:Base Sequence; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D014407:Tumor Cells, Cultured