Newcastle disease virus induced ferroptosis through p53-SLC7A11-GPX4 axis mediated nutrient deprivation in tumor cells

Abstract

SummaryA number of new cell death processes have been discovered in recent years, including ferroptosis, which is characterized by the accumulation of lipid peroxidation products derived from iron metabolism. The evidence suggests that ferroptosis has a tumor-suppressor function. However, the mechanism by which ferroptosis mediates the response of tumor cells to oncolytic viruses remains poorly understood. Newcastle disease virus can selectively replicate in tumor cells. We show that NDV-induced ferroptosis acts through p53-SLC7A11-GPX4 pathway. The expression of tumor suppressor gene p53 increased after NDV infection, and the expressions of SLC7A11 and SLC3A2 were down-regulated, leading to the inhibition of glutathione synthesis and a decrease in glutathione peroxidase 4 expression. The chemical compound erastin, which induces ferroptosis, also down-regulated glutathione synthase expression and caused lipid peroxide accumulation and cell death. Meanwhile, the levels of intracellular reactive oxygen species and lipid peroxides increased in tumor cells. Ferritinophagy was induced by NDV promotion of ferroptosis through the release of ferrous iron and an enhanced Fenton reaction. Collectively, these observations demonstrated that NDV can kill tumor cells through ferroptosis. Our study provides novel insights into the mechanisms of NDV-induced ferroptosis and highlights the critical role of viruses in treating therapy-resistant cancers.

2-Deoxyglucose Glycolysis Inhibitor Augment Oncolytic Virotherapy to Induce Oxidative Stress and Apoptosis in Breast Cancer (Part Ⅲ)

“…In addition, breast cancer cell which exposed to 2DG showed a reduction in total glutathione and elevation in glutathione disulfide and lipid peroxidation (36). Recently, work documented that NDV impedes glutathione synthesis, glutathione peroxidase down-expression, and ROS accumulation in the cancer cells (37). Thus, current results indicate that combination therapy decreases the metabolism of glucose lead to T-GSH depletion and elevation of ROS.…”

“…The current result showed that combination therapy induces a higher apoptosis rate than NDV alone or 2DG alone. NDV had several mechanisms for inducing apoptosis, including endoplasmic reticulum pathway, ferroptosis, caspase-dependent and caspase-independent pathways (28,37,39). In addition, 2DG induces ER stress-induced apoptosis by protein N-glycosylation disrupting (40).…”