Anti-PTGR1 monoclonal antibody, clone FQS24562-21

Prostanoids derived from the activity of cyclooxygenases and their respective synthases contribute to both active inflammation and immune response in the tumor microenvironment. Their synthesis, deactivation and role in glioma biology have not yet been fully explored and require further study. Using quantitative real time PCR, gas chromatography/electron impact mass spectrometry and liquid chromatography/electrospray ionization tandem mass spectrometry, we have further characterized the prostanoid pathway in grade IV glioblastoma (GBM). We observed significant correlations between high mRNA expression levels and poor patient survival for microsomal PGE synthase 1 (mPGES1) and prostaglandin reductase 1 (PTGR1). Conversely, high mRNA expression levels for 15-hydroxyprostaglandin dehydrogenase (15-HPGD) were correlated with better patient survival. GBMs had a higher quantity of the prostanoid precursor, arachidonic acid, versus grade tumors and in GBMs a significant positive correlation was found between arachidonic acid and PGE(2) content. GBMs also had higher concentrations of TXB2, PGD(2), PGE(2) and PGF(2 alpha) versus grade II/III tumors. A significant decrease in survival was detected for high versus low PGE(2), PGE(2) + PGE(2) deactivation products (PGEMs) and PGF(2) in GBM patients. Our data show the potential importance of prostanoid metabolism in the progression towards GBM and provide evidence that higher PGE(2) and PGF(2 alpha), concentrations in the tumor are correlated with poorer patient survival. Our findings highlight the potential importance of the enzymes 15-HPGD and PTGR1 as prognostic biomarkers which could be used to predict survival outcome of patients with GBM.

Prostaglandin reductase-1 (Ptgrl) is an alkenal/one oxidoreductase that is involved in the catabolism of eicosanoids and lipid peroxidation such as 4-hydroxynonenal (4-HNE). Recently, we reported that Ptgrl is overexpressed in human clinical and experimentally induced samples of hepatocellular carcinoma (HCC). However, how the expression of this gene is regulated and its role in carcinogenesis are not yet known. Here, we studied parameters associated with antioxidant responses and the mechanisms underlying the induction of Ptgrl expression by the activation of Nuclear Factor (erythroid-derived-2)-like-2 (NRF2). For these experiments, we used two protocols of induced hepatocarcinogenesis in rats. Furthermore, we determined the effect of PTGR1 on cell proliferation and resistance to oxidative stress in cell cultures of the epithelial liver cell line, C9. Ptgrl was overexpressed during the early phase in altered hepatocyte foci, and this high level of expression was maintained in persistent nodules until tumors developed. Ptgrl expression was regulated by NRF2, which bound to an antioxidant response element at -653 bp in the rat Ptgrl gene. The activation of NRF2 induced the activation of an antioxidant response that included effects on proteins such as glutamate-cysteine ligase, catalytic subunit, NAD(P)H dehydrogenase quinone-1 (NQO1) and glutathione-S-transferase-P (GSTP1). These effects may have produced a reduced status that was associated with a high proliferation rate in experimental tumors. Indeed, when Ptgrl was stably expressed, we observed a reduction in the time required for proliferation and a protective effect against hydrogen peroxide-and 4-HNE-induced cell death. These data were consistent with data showing colocalization between PTGR1 and 4-HNE protein adducts in liver nodules. These findings suggest that Ptgrl and antioxidant responses act as a metabolic adaptation and could contribute to proliferation and cell-death evasion in liver tumor cells. Furthermore, these data indicate that Ptgrl could be used to design early diagnostic tools or targeted therapies for HCC.