Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma

Abstract

Regulation of oxidative stress and redox systems has important roles in carcinogenesis and cancer progression, and for this reason has attracted much attention as a new area of cancer therapeutic targets. Glutathione peroxidase 4 (GPX4), an antioxidant enzyme, has biological important functions such as signaling cell death by suppressing peroxidation of membrane phospholipids. However, few studies exist on the expression and clinical relevance of GPX4 in malignant lymphomas such as diffuse large B-cell lymphoma. In this study, we assessed the expression of GPX4 immunohistochemically. GPX4 was expressed in 35.5% (33/93) cases of diffuse large B-cell lymphoma. The GPX4-positive group had poor overall survival (P = 0.0032) and progression-free survival (P = 0.0004) compared with those of the GPX4-negative group. In a combined analysis of GPX4 and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, there was a negative correlation between GPX4 and 8-hydroxydeoxyguanosine (P = 0.0009). The GPX4-positive and 8-hydroxydeoxyguanosine-negative groups had a significantly worse prognosis than the other groups in both overall survival (P = 0.0170) and progression-free survival (P = 0.0005). These results suggest that the overexpression of GPX4 is an independent prognostic predictor in diffuse large B-cell lymphoma. Furthermore, in vitro analysis demonstrated that GPX4-overexpressing cells were resistant to reactive oxygen species-induced cell death (P = 0.0360). Conversely, GPX4-knockdown cells were sensitive to reactive oxygen species-induced cell death (P = 0.0111). From these data, we conclude that GPX4 regulates reactive oxygen species-induced cell death. Our results suggest a novel therapeutic strategy using the mechanism of ferroptosis, as well as a novel prognostic predictor of diffuse large B-cell lymphoma.

Hepatitis B virus surface protein induces oxidative stress by increasing peroxides and inhibiting antioxidant defences in human spermatozoa

“…Deletion of the selenoprotein GPX4 in spermatocytes results in male infertility in mice (Imai et al 2009). Recently, it was shown that overexpression of GPX4 inhibits peroxide-induced cell death in diffuse large B cell lymphoma (Kinowaki et al 2018). Members of the PRDX family can reduce a variety of ROS, including H 2 O 2 , organic hydroperoxides and ONOO-(O'Flaherty 2014a).…”

The Evaluation of Oxidative Stress and High-Density Lipoprotein Cholesterol Levels in Diffuse Large B-Cell Lymphoma

“…In a large multicenter case-control study, Wang et al genotyped 13 single nucleotide polymorphisms from 10 oxidative stress genes (AKR1A1, AKR1C1, CYBA, GPX, MPO, NOS2A, NOS3, OGG1, PPARG and SOD2) to determine whether these genes influence the risk for NHL, and reported that genetic variations that result in an increased generation of ROS seem to increase the risk for NHL and its major subtypes, particularly DLBCL [29]. Moreover, the overexpression of glutathione peroxidase 4 (GPX4) in DLBCL, as pointed out by Kinowaki et al, is associated with a poor prognosis, since it prevents ROS-mediated cell death [30].…”

Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule

“…Besides promoting ferroptosis via ferritinophagy and lipid hydroperoxidation, MIOX overexpression may also inhibit the "ferroptosis termination system" by downregulating GPX4 activity and intracellular GSH concentration. Normally, the key anti oxidase GPX4, together with GSH, catalyzes noxious lipid hydroperoxides into harmless lipid alcohols, leading to the end of ferroptosis (44). Therefore, it is conceivable that GPX4 inhibitors and system X c antagonists (related to GSH depletion) can serve as ferroptosis inducers (45,46).…”