Glutathione peroxidase-1 regulates ASK1-dependent apoptosis via interaction with TRAF2 in RIPK3-negative cancer cells

Abstract

Cancer: Antioxidative enzyme protects tumor cells from programmed death An antioxidative enzyme that plays a critical role in regulating whether cells program their own death offers a promising new target for anti-cancer therapies. Glutathione peroxidase-1 (GPX1) is involved in cleaning up reactive metabolic byproducts such as hydrogen peroxide inside cells. Sang Won Kang and colleagues at Ewha Womans University in Seoul, South Korea, showed that this stress-response enzyme also suppresses the induction of normal programmed cell death mechanisms in a variety of cancer cells. The researchers detailed the molecular partners involved in GPX1-mediated signaling inside cancer cells, and demonstrated that genetically reducing GPX1 expression dramatically reduces tumor growth in a mouse model of breast cancer. Drugs with similar inhibitory effects on GPX1 activity might therefore also help shrink tumors in human cancer patients. Glutathione peroxidase (GPx) is a selenocysteine-containing peroxidase enzyme that defends mammalian cells against oxidative stress, but the role of GPx signaling is poorly characterized. Here, we show that GPx type 1 (GPx1) plays a key regulatory role in the apoptosis signaling pathway. The absence of GPx1 augmented TNF-alpha-induced apoptosis in various RIPK3-negative cancer cells by markedly elevating the level of cytosolic H2O2, which is derived from mitochondria. At the molecular level, the absence of GPx1 led to the strengthened sequential activation of sustained JNK and caspase-8 expression. Two signaling mechanisms are involved in the GPx1-dependent regulation of the apoptosis pathway: (1) GPx1 regulates the level of cytosolic H2O2 that oxidizes the redox protein thioredoxin 1, blocking ASK1 activation, and (2) GPx1 interacts with TRAF2 and interferes with the formation of the active ASK1 complex. Inducible knockdown of GPx1 expression impaired the tumorigenic growth of MDA-MB-231 cells (>70% reduction, P = 0.0034) implanted in mice by promoting apoptosis in vivo. Overall, this study reveals the apoptosis-related signaling function of a GPx family enzyme highly conserved in aerobic organisms.