Disease relevance of GPX4

• These results confirm a role for selenium in risk of lung cancer and the independent regulation of GPX1 and GPX4 [1].
• Our results show that two of the glutathione peroxidase family members (GPX1 and GPX4) are highly induced by supplemental selenium in prostate cancer cells but only slightly induced in RWPE-1 cells [2].
• The Se-deficient diet caused significant decreases in GPx activity and cGPx mRNA expression but no change in PHGPx mRNA, together with significant proteinuria and glucosuria and slight decline in Ccr [3].

High impact information on GPX4

• The 26- and 21-kDa proteins were identified in immunoblot assays as the glutathione peroxidase (cGPX or GPX1) subunit and phospholipid hydroperoxide glutathione peroxidase (PHGPX or GPX4), respectively [4].
• Phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide in mammalian cells [5].
• Located predominantly in mitochondria of 7G4 cells, GPX4 strongly inhibited both LOOH accumulation and apoptosis under protocol-1 conditions, but had no significant effect under protocol-2 conditions [6].
• Hyperresistance to photosensitized lipid peroxidation and apoptotic killing in 5-aminolevulinate-treated tumor cells overexpressing mitochondrial GPX4 [6].
• Also, in contrast with Se-PHGPx, only glutathione could act as the reducing agent for GST A1-1 [7].

Biological context of GPX4

• The expression of snPHGPx has been attributed either to an alternative pre-mRNA splicing or to the presence of a distinct promoter region [8].
• Metamorphosis of the selenoprotein PHGPx during spermatogenesis [9].
• MATERIALS AND METHODS: Phospholipid hydroperoxide glutathione peroxidase (PHGPx or GPx4), which metabolizes peroxidized phospholipids, was cloned in an expression plasmid, transfected in HT29 cl.19A colon carcinoma cells and the effects of PHGPx overexpression were measured on arachidonic acid metabolism by COX-2 [10].
• Transfection of the endothelial cell line ECV 304 with either PHGPx cDNA or SelD cDNA did not result in a substantial increase of PHGPx activities, independent of selenium supply [11].

Anatomical context of GPX4

• The pivotal link between Se, sperm quality and male fertility is GPX4 since the enzyme is essential to allow the production of the correct architecture of the midpiece of spermatozoa [12].
• CONCLUSION: In endothelial cells, sulforaphane increases TR-1 but not GPX-1 and GPX-4 and in doing so confers protection against oxidative damage induced by lipid hydroperoxides [13].
• The aim of this study was to investigate the role of coenzyme Q on the mRNA abundance of PHGPx and the reactive oxygen species (ROS) production in two different cell lines from human prostate, a line of non cancer cells (PNT2) and a line of cancer cells (PC3) [14].

Associations of GPX4 with chemical compounds

• The biological roles of the essential micronutrient Se are attributed to its presence in a range of 20-30 selenoproteins including the cytosolic and phospholipid hydroperoxide glutathione peroxidases (GPX1 and GPX4) [15].
• Sulforaphane induced TR-1 expression in selenium-deficient cells (1.83 +/- 0.11 fold, P < 0.001) and selenium-supplemented cells (2.90 +/- 0.17 fold, P < 0.001) but had no inductive effect on GPX-1 or GPX-4 [13].
• RESULTS: Selenite treatment increased the concentration of TR-1 (1.6 +/- 0.17 fold, P < 0.05), GPX-1 activity (8.2 +/- 1.08 fold, P < 0.001), and GPX-4 activity (3.1 +/- 0.25 fold, P < 0.001) [13].
• Results showed that malignant cells markedly differ in their response to coenzyme Q compared to non-malignant cells, with no changes in PHGPx expression and greater ROS production [14].

Other interactions of GPX4

• On the basis of these results, we demonstrate that snPHGPx expression is mediated by the transcription factor CREM-tau, which acts as a cis-acting element localized in the first intron of the PHGPx gene [8].
• In the familiy of selenium-dependent glutathione peroxidases (GPx) the ranking is GI-GPx > or = PHGPx > cGPx = pGPx [16].
• OBJECTIVE: To determine the expression and enzymatic activity of glutathione peroxidase (GPX)-1, GPX-4, and glutathione reductase together with glutathione (GSH) concentrations in spermatozoa from fertile and infertile men [17].
• METHODS: EAhy926 cells were supplemented with 40 nM of selenite and/or sulforaphane (10 muM) for 72 h and the expression of TR-1, GPX-1, and GPX-4 was assessed [13].
• All of these derive from the same gene and are structurally related with the exception of the snPHGPx (sperm nucleus-specific form), which differs from the others due to the presence of an arginine-rich N-terminus [8].

Analytical, diagnostic and therapeutic context of GPX4

• Northern blot analysis indicated that the increase in GPX activities was due to increased transcript levels of GPX1 but not GPX4 in both cells [18].
• Further support derived from site-specific effects observed using (i) a mitochondrial GPX4-overexpressing clone (7G4) of COH-BR1 tumor cells, and (ii) an ALA treatment protocol in which most cellular PpIX is either inside (Pr-1) or outside (Pr-2) mitochondria [19].

References