Ferroptosis in glioma
Ferroptosis role in glioma cell death remains unclear.
The prognostic value of ferroptosis-related genes was investigated in low-grade gliomas (LGG).
Zheng et al. downloaded the ferroptosis-related genes from the FerrDb dataset. Univariate Cox and LASSO regression analyses were applied to identify genes correlated with overall survival (OS). Subsequently, 12 ferroptosis-related genes were screened to establish the prognostic signature using stepwise multivariate Cox regression. According to the median value of risk scores, patients were divided into low- and high-risk subgroups. The Kaplan-Meier curves showed the high-risk group had a lower OS. The predictive power of the risk model was validated using the CGGA. Functional analysis revealed that the terms associated with plasma membrane receptor complex, immune response and glutamate metabolic process were primarily related to the risk model. Moreover, we established a nomogram that had a strong forecasting ability for the 1-, 3- and 5-year OS. In addition, we compared the risk scores between different clinical features. We also detected infiltration of macrophages and monocytes in different subgroups. Overall, our study identified the prognostic signature of 12 ferroptosis-related genes, which has the potential to predict the prognosis of LGG 1).
Wang et al. found Pseudolaric acid B (PAB) inhibited the viabilities of glioma cells in vitro and in vivo, which was accompanied by abnormal increases of intracellular ferrous iron, H2O2 and lipid peroxidation, as well as depletion of GSH and cysteine. In vitro studies revealed that the lipid peroxidation and the cell death caused by PAB were both inhibited by iron chelator deferoxamine, but exacerbated by supplement of ferric ammonium citrate. Inhibition of lipid peroxidation with ferrostatin-1 or GSH rescued PAB-induced cell death. Morphologically, the cells treated with PAB presented intact membrane, shrunken mitochondria with increased membrane density, and normal-sized nucleus without chromatin condensation. Mechanistically, PAB improved intracellular iron by upregulation of transferrin receptor. The increased iron activated Nox4, which resulted in overproduction of H2O2 and lipid peroxides. Moreover, PAB depleted intracellular GSH via p53-mediated xCT pathway, which further exacerbated accumulation of H2O2 and lipid peroxides. Thus, PAB triggers ferroptosis in glioma cells and is a potential medicine for glioma treatment 2).
Fan et al. show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, Glioblastoma) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system Xc-) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles' heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics 3).