Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells

Bai, Tao; Wang, Shuai; Zhao, Yipu; Zhu, Ruijie; Wang, Weijie; Sun, Yuling

doi:10.1016/j.bbrc.2017.07.136

Cited by 118 publications

(92 citation statements)

References 39 publications

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“…27 In this study, knockdown of S1R significantly increased Fe 2+ levels in HCC cells treated with erastin and sorafenib compared with the control counterpart ( Figure 4C). Similar to our previous study, 21 another two S1R antagonists (BD1063 and BD1047) increased erastin-and sorafenib-induced MDA production and Fe 2+ levels (Figure 4E,F).…”

Section: S1r Protects Against Ferroptosis In Hcc Cellssupporting

confidence: 90%

“…Similar to our previous study, 21 another two S1R antagonists (BD1063 and BD1047) 26 increased sorafenib-induced HCC cell death, while the S1R agonist PRE-084 had no effect on cell death ( Figure 3D). In general, these findings demonstrate that S1R inhibition increases the sensitivity of HCC cells to sorafenib.…”

Section: Suppression Of S1r Expression Increases the Sorafenib Senssupporting

confidence: 89%

“…and Huh-7 cells ( Figure 1A,B). 21 Furthermore, sorafenib up-regulated S1R protein levels in these HCC cells in a time-dependent manner ( Figure 1A-D). Then, Huh-7 cells were treated with or without sorafenib and ferrostatin-1 (a ferroptosis inhibitor), and immunofluorescence staining was performed.…”

Section: Sorafenib Induces S1r Protein Expression In Human Hcc Cellsmentioning

confidence: 89%

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Sigma‐1 receptor protects against ferroptosis in hepatocellular carcinoma cells

Bai

Lei

Zhou

et al. 2019

J Cellular Molecular Medi

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125

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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.

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Section: S1r Protects Against Ferroptosis In Hcc Cellssupporting

confidence: 90%

Section: Suppression Of S1r Expression Increases the Sorafenib Senssupporting

confidence: 89%

Section: Sorafenib Induces S1r Protein Expression In Human Hcc Cellsmentioning

confidence: 89%

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Sigma‐1 receptor protects against ferroptosis in hepatocellular carcinoma cells

Bai

Lei

Zhou

et al. 2019

J Cellular Molecular Medi

Self Cite

125

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“…Interestingly, we found that haloperidol potently upregulates Sigmar1 at the protein level, with no significant changes in its transcription (transcriptional data not shown). This has been previously observed in hepatocellular carcinoma and neuronal cells (42,71), but to our knowledge not reported in fibroblasts so far. Our data suggest that the binding of haloperidol to Sigmar1 might induce the release of calcium from the ER into the cytosol, thereby promoting ER stress, which could in turn upregulate Sigmar1 levels.…”

Section: Discussionsupporting

confidence: 67%

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

Rehman¹,

Vodret²,

Braga³

et al. 2019

JCI Insight

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“…Erastin was identified as a cell death inducer in 2003 (Dolma, Lessnick, Hahn, & Stockwell, 2003) before the notion of ferroptosis was named by Dixon et al in 2012 (Dixon et al, 2012). We and others (Bai et al, 2017; Sun et al, 2016) demonstrated that erastin could induce death in HepG2 and Hep3B cells successfully. These findings indicate that hepatoma cells are susceptible to ferroptosis inducer.…”

Section: Discussionmentioning

confidence: 75%

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

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107

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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 Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre‐miR‐214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR‐214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR‐214‐induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR‐214 elevated the ferroptosis‐promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis‐promoting effects of miR‐214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

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Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells

Cited by 118 publications

References 39 publications

Sigma‐1 receptor protects against ferroptosis in hepatocellular carcinoma cells

Sigma‐1 receptor protects against ferroptosis in hepatocellular carcinoma cells

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

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