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.

An 8-gene signature, including methylated and down-regulated glutathione peroxidase 3, of gastric cancer

“…This is expected since, in our case it was selected from the comparison of noncancerous gastric tissues and heterogeneous (tumor stage, intestinal, diffuse types combined) gastric cancer tissues. It is comparable to the case in prostate cancer, where the difference in survival of the patients based on GPX3 expression was not associated with Gleason's grade, but with the relapse of prostate cancer (14). We have shown that GPX3 is down-regulated in gastric cancer primarily due to promoter methylation.…”

“…Pubmed and public microarray database searches confirm the altered expression for these genes in several cancer models, for example methylation and down-regulation of GPX3 (14)(15)(16)(17), SST (18-21) and KLF4 (22)(23)(24)(25) in cancer compared with corresponding non-cancerous counterparts. Likewise, the up-regulation of THY1 in colon cancer microarray study together with real-time reverse transcription-PCR validation has been reported before (26), but there is also a report on the down-regulation of THY1 in metastatic nasopharyngeal carcinoma (27).…”

“…The development of diagnostic tools, based on the molecular markers, which are less invasive and less expensive, has the potential to aid in the early detection of gastric cancer, together with the currently used endoscopy, therefore, leading to a better chance for appropriate treatment (14). In addition, these bio-markers serve as critical tools in understanding carcinogenesis at a molecular level.…”

p53-induced Gene 3 Mediates Cell Death Induced by Glutathione Peroxidase 3

“…However, increasing evidence suggests that GPx3 also possesses tumor suppressor activity (5,9,(22)(23)(24)(25)(26)(27)(28)(29). In this study, GPx3 carries out tumor suppressor signaling at least partly through the activation of PIG3, which is a protein associated with the generation of ROS that induces cell death.…”

“…In addition, the down-regulation of GPx3 was found closely associated with cancer progression (12). Forced expressions of GPx3 in prostate cancer cell lines PC3 (androgen-insensitive), DU145 (androgen-insensitive), and LNCaP (androgen-sensitive) in the absence of oxidative stress were shown to be associated with a reduction of tumor growth and a decrease in tumor metastasis in SCID mice (9). GPx3 contains a selenocysteine encoded by a UGA opal codon (13), which requires selenium to translate GPx3 to a full-length and enzymatically active protein.…”