erastin and Carcinoma--Hepatocellular

The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

Topics: Animals; Antibodies, Neutralizing; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Down-Regulation; Ferroptosis; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Leukemia Inhibitory Factor Receptor alpha Subunit; Lipocalin-2; Liver Neoplasms; Male; Mice, Inbred C57BL; NF-kappa B; Piperazines; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; Sorafenib; Up-Regulation; Xenograft Model Antitumor Assays

Primary liver cancer is the second most frequent cause of cancer-related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA-214-3p (miR-214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR-214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR-214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre-miR-214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti-miR-214 sponge showed the opposite effect. Additionally, pre-miR-214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe

Topics: Activating Transcription Factor 4; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Ferroptosis; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; MicroRNAs; Piperazines; Reactive Oxygen Species

Ferroptosis is a form of regulated cell death induced by lipid peroxidation that is dependent on iron. This pathway is being considered as an alternative anticancer therapeutic strategy, and the chemoreagent erastin induces ferroptosis by blocking system Xc

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Down-Regulation; Ferroptosis; Fibrosarcoma; Gene Knockdown Techniques; Humans; Isocitrate Dehydrogenase; Mice; Piperazines

Ferroptosis is a regulated form of cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Ceruloplasmin (CP) is a glycoprotein that plays an essential role in iron homeostasis. However, whether CP regulates ferroptosis has not been reported. Here, we show that CP suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma (HCC) cells. Depletion of CP promoted erastin- and RSL3-induced ferroptotic cell death and resulted in the accumulation of intracellular ferrous iron (Fe

Topics: Antigens, CD; Carbolines; Carcinoma, Hepatocellular; Cation Transport Proteins; Cell Line, Tumor; Ceruloplasmin; Ferroptosis; Frameshift Mutation; Homeostasis; Humans; Iron; Liver Neoplasms; Models, Biological; Piperazines; Receptors, Transferrin

In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC.. Integrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes.. Four genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy.. The prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients. Video Abstract.

Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Disease Progression; Ferroptosis; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Iron; Kaplan-Meier Estimate; Liver Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Nomograms; Piperazines; Prognosis; Regression Analysis; Reproducibility of Results; Risk Factors; Tumor Microenvironment

Sigma-1 receptor (S1R) regulates reactive oxygen species (ROS) accumulation via nuclear factor erythroid 2-related factor 2 (NRF2), which plays a vital role in ferroptosis. Sorafenib is a strong inducer of ferroptosis but not of apoptosis. However, the mechanism of sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC) remains unclear. In this study, we found for the first time that sorafenib induced most of S1Rs away from nucleus compared to control groups in Huh-7 cells, and ferrostatin-1 completely blocked the translocation. S1R protein expression, but not mRNA expression, in HCC cells was significantly up-regulated by sorafenib. Knockdown of NRF2, but not of p53 or hypoxia-inducible factor 1-alpha (HIF1α), markedly induced S1R mRNA expression in HCC cells. Inhibition of S1R (by RNAi or antagonists) increased sorafenib-induced HCC cell death in vitro and in vivo. Knockdown of S1R blocked the expression of glutathione peroxidase 4 (GPX4), one of the core targets of ferroptosis, in vitro and in vivo. Iron metabolism and lipid peroxidation increased in the S1R knockdown groups treated with sorafenib compared to the control counterpart. Ferritin heavy chain 1 (FTH1) and transferrin receotor protein 1 (TFR1), both of which are critical for iron metabolism, were markedly up-regulated in HCC cells treated with erastin and sorafenib, whereas knockdown of S1R inhibited these increases. In conclusion, we demonstrate that S1R protects HCC cells against sorafenib and subsequent ferroptosis. A better understanding of the role of S1R in ferroptosis may provide novel insight into this biological process.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Death; Cell Line, Tumor; Ferroptosis; Hep G2 Cells; Humans; Lipid Peroxidation; Liver Neoplasms; Mice; Piperazines; Reactive Oxygen Species; Receptors, sigma; Sigma-1 Receptor; Sorafenib; Up-Regulation

Ferroptosis is a non-apoptotic, iron-dependent oxidative form of cell death that is specifically induced by erastin in RAS mutant cancer cells. Ferroptotic cell death is the result of membrane lipid peroxide damage caused by the accumulation of hydroxyl radicals derived from H

Topics: Carcinoma, Hepatocellular; Ferroptosis; GA-Binding Protein Transcription Factor; Hep G2 Cells; Humans; Liver Neoplasms; Neoplasm Proteins; Oxidative Stress; Peroxiredoxins; Piperazines; RNA, Long Noncoding; RNA, Neoplasm

Ferroptosis is a novel form of cell death, which is characterized by accumulation of reactive oxygen species (ROS). Sigma 1 receptor (S1R) has been suggested to function in oxidative stress metabolism. Both erastin and sorafenib significantly induced S1R protein expression. Haloperidol strongly promoted erastin- and sorafenib-induced cell death, which was blocked by ferrostatin-1 but not ZVAD-FMK or necrosulfonamide. During ferroptosis, haloperidol substantially increased the cellular levels of Fe

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Survival; Dose-Response Relationship, Drug; Haloperidol; Humans; Iron; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Piperazines; Receptors, sigma; Sigma-1 Receptor; Sorafenib; Structure-Activity Relationship; Tumor Cells, Cultured

Respiratory substrates and adenine nucleotides cross the mitochondrial outer membrane through the voltage-dependent anion channel (VDAC), comprising three isoforms--VDAC1, 2, and 3. We characterized the role of individual isoforms in mitochondrial metabolism by HepG2 human hepatoma cells using siRNA. With VDAC3 to the greatest extent, all VDAC isoforms contributed to the maintenance of mitochondrial membrane potential, but only VDAC3 knockdown decreased ATP, ADP, NAD(P)H, and mitochondrial redox state. Cells expressing predominantly VDAC3 were least sensitive to depolarization induced by increased free tubulin. In planar lipid bilayers, free tubulin inhibited VDAC1 and VDAC2 but not VDAC3. Erastin, a compound that interacts with VDAC, blocked and reversed mitochondrial depolarization after microtubule destabilizers in intact cells and antagonized tubulin-induced VDAC blockage in planar bilayers. In conclusion, free tubulin inhibits VDAC1/2 and limits mitochondrial metabolism in HepG2 cells, contributing to the Warburg phenomenon. Reversal of tubulin-VDAC interaction by erastin antagonizes Warburg metabolism and restores oxidative mitochondrial metabolism.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Carcinoma, Hepatocellular; Gene Knockdown Techniques; Hep G2 Cells; Humans; Lipid Bilayers; Liver Neoplasms; Mitochondria; Mitochondrial Proteins; NADP; Neoplasm Proteins; Oxidation-Reduction; Piperazines; Tubulin; Voltage-Dependent Anion Channels