Sigma‐1 receptor protects against ferroptosis in hepatocellular carcinoma cells

Bai, Tao; Lei, Pengxu; Zhou, Hao; Liang, Ruopeng; Zhu, Ruijie; Wang, Weijie; Zhou, Lin; Sun, Yuling

doi:10.1111/jcmm.14594

Cited by 114 publications

(74 citation statements)

References 36 publications

(112 reference statements)

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“…Because genes might either facilitate or suppress ferroptosis, the transcriptional changes of SOFs and DOFs in the CIFI-stratified subgroups were investigated. ATF4, CA9, EGLN1, ELAVL1, FTH1, GPX4, HELLS, ITGB8, NFE2L2, SLC7A11, SQSTM1, and VDAC2 are well-investigated SOFs ( Dixon et al, 2012 ; Sun et al, 2016b ; Chen et al, 2017 ; Jiang et al, 2017 ; Zhang et al, 2018 ; Bai et al, 2019 ; Li et al, 2019 ). It was found that, excluding GPX4, NFE2L2, and SQSTM1, the remaining SOFs were significantly up-regulated in the high-CIFI subgroup of the GSE14520 cohort ( Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

“…Consequently, ferroptosis, a biological process in which immune therapy and sorafenib converge to exert an anti-tumor effect, might have a fundamental impact on the treatment response of HCC. The understanding of the occurrence and regulation of ferroptosis has increased considerably in recent decades; however, only a few studies have explored the ferroptosis-related genes (FRGs) and pathways in HCC ( Louandre et al, 2013 , 2015 ; Carlson et al, 2016 ; Houessinon et al, 2016 ; Sun et al, 2016b ; Bai et al, 2019 ; Qi et al, 2019 ; Feng et al, 2020 ; Kim et al, 2020 ). With the currently available FRGs and immune-related genes (IRGs), and the accumulative data deposited in public databases like The Cancer Genome Atlas (TCGA), it is hypothesized that a prognostic molecular classifier based on the immune response and ferroptosis status might help to identify subgroups of HCC patients with distinct ferroptosis-immune phenotypes and survival profiles.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma

Liu

Zhang

et al. 2020

Front. Cell Dev. Biol.

100

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BackgroundImmunotherapy and sorafenib exert anti-tumor effects via ferroptosis, but reliable biomarkers for the individual treatment and prognosis prediction of hepatocellular carcinoma (HCC) based on the ferroptosis and immune status remain lacking.MethodsFerroptosis-related genes (FRGs) were identified by downloading data from FerrDb and by searching and reading original articles from PubMed. Immune-related genes (IRGs) were downloaded from ImmPort. Prognostic FRGs and IRGs in the GSE14520 (n = 220) and The Cancer Genome Atlas (TCGA, n = 365) datasets were identified. Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression were used for model construction. Ferroptosis expression profiles, the infiltration of immune cells, and the somatic mutation status were analyzed and compared.ResultsTwenty-seven prognostic ferroptosis- and immune-related signatures were included to construct a comprehensive index of ferroptosis and immune status (CIFI). A subgroup of patients was identified as having a high CIFI value, which was associated with a worse prognosis. This subgroup of patients had significantly up-regulated expressions of many suppressors of ferroptosis and higher fractions of immunosuppressive cells, such as cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs). Notably, somatic mutation analysis indicated that high-CIFI patients had higher levels of tumor heterogeneity and higher mutation frequencies of genes like TP53.ConclusionIn this work, a novel prognostic classifier was developed based on ferroptosis- and IRGs in HCC, and this classifier could be used for prognostic prediction and the selection of patients for immunotherapies and targeted therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma

Liu

Zhang

et al. 2020

Front. Cell Dev. Biol.

100

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“…In addition, Sigma 1 receptor (S1R) is abundantly expressed in hepatocytes. Inhibition of this receptor also promotes ferroptosis in HCC cells 38,39 . Furthermore, there are many negative regulators of ferroptosis in HCC, such as nuclear factor erythroid 2related factor 2 (NRF2), metallothionein-1G (MT-1G), CDGSH iron-sulfur domain 1 (CISD1) and P53.…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 97%

Ferroptosis: past, present and future

et al. 2020

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Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases. Facts Ferroptosis is a new type of programmed cell death, which occurs with iron dependence. Ferroptosis plays an important regulatory role in the occurrence and development of many diseases, such as tumors, neurological diseases, acute kidney injury, ischemia/reperfusion, etc. Activating or blocking the ferroptosis pathway to alleviate the progression of the disease, which provides a promising therapeutic strategy for many diseases. Open questions What is the relationship between ferroptosis and other types of cell death? Is it synergy or antagonism? Is iron necessary to promote the production of lipid peroxides, or can other substances take the place of iron in ferroptosis? What is the downstream regulation mechanism of iron in ferroptosis? How can ferroptosis promote the development of inflammation?

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“…All these proteins are closely related to ferroptosis. 22 ATF4 is commonly expressed in human organs and can be activated in response to various stress signals including hypoxia, endoplasmic reticulum stress, amino acid deprivation, and oxidative stress. High expression of ATF4 is known to be related to the growth of malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

Matrine Can Inhibit the Growth of Colorectal Cancer Cells by Inducing Ferroptosis

Wang

Tang

Cai

et al. 2020

Natural Product Communications

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Colorectal cancer (CRC) is a common malignant tumor of the digestive system that can seriously threaten human health. Chinese matrine is known to have a wide range of antiviral and immunomodulatory effects. In this study, we evaluated the effect of matrine on ferroptosis using the HCT116 human colon cancer cell line. We evaluated cell viability and proliferation using the cell counting kit-8 assay and carried out cell clone formation experiment by measuring reactive oxygen species (ROS) production, as well as levels of glutathione (GSH), lipid peroxide (MDA), Fe2+, glutathione peroxidase 4 (GPX4), activating transcription factor 4 (ATF4), solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein 2 (TFR2), and Sigma-1 receptor (Sigma-1R) in order to evaluate the redox status of cells. These results indicate that matrine can significantly reduce the cell viability of HCT116 and decrease cell proliferation. After treatment with matrine, ROS, Fe2+, and MDA levels increased significantly, while the GSH content decreased. In addition, the expression of GPX4, SLC7A11, and Sigma-1R decreased significantly, while the expression of ATF4 and TFR2 increased significantly. These results indicate that matrine can induce ferroptosis in CRC, which can provide new clues for further pharmacological research of matrine and provide experimental evidence for understanding its mechanism of inhibiting CRC.

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Sigma‐1 receptor protects against ferroptosis in hepatocellular carcinoma cells

Cited by 114 publications

References 36 publications

Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma

Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma

Ferroptosis: past, present and future

Matrine Can Inhibit the Growth of Colorectal Cancer Cells by Inducing Ferroptosis

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