Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis.
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.
Yu
Yan P
YP
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Yu
Guoying
G
Tseng
George
G
Cieply
Kathleen
K
Nelson
Joel
J
Defrances
Marie
M
Zarnegar
Reza
R
Michalopoulos
George
G
Luo
Jian-Hua
JH
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