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Daolin Tang - One of the best experts on this subject based on the ideXlab platform.
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NUPR1 is a critical repressor of Ferroptosis
Nature Communications, 2021Co-Authors: Jiao Liu, Xinxin Song, Yangchun Xie, Feimei Kuang, Qiuhong Zhang, Rui Kang, Guido Kroemer, Daolin TangAbstract:Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in Ferroptosis, although the key regulator for Ferroptosis in iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, a stress-inducible transcription factor, as a driver of Ferroptosis resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic cell death through diminishing iron accumulation and subsequent oxidative damage. Consequently, LCN2 depletion mimics NUPR1 deficiency with respect to Ferroptosis induction, whereas transfection-enforced re-expression of LCN2 restores resistance to Ferroptosis in NUPR1-deficient cells. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn2 conditional knockout mice, or the small molecule ZZW-115) increases the activity of the Ferroptosis inducer erastin and worsens pancreatitis, in suitable mouse models. These findings suggest a link between NUPR1-regulated iron metabolism and Ferroptosis susceptibility.
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Ferroptosis molecular mechanisms and health implications
Cell Research, 2021Co-Authors: Rui Kang, Daolin Tang, Xin Chen, Guido KroemerAbstract:Cell death can be executed through different subroutines. Since the description of Ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of Ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, Ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of Ferroptosis and describe how dysregulated Ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.
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broadening horizons the role of Ferroptosis in cancer
Nature Reviews Clinical Oncology, 2021Co-Authors: Xin Chen, Rui Kang, Guido Kroemer, Daolin TangAbstract:The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, Ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce Ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which Ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate Ferroptosis. Herein, we present the key molecular mechanisms of Ferroptosis, describe the crosstalk between Ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of Ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.
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tumor heterogeneity in autophagy dependent Ferroptosis
Autophagy, 2021Co-Authors: Jiao Liu, Xinxin Song, Rui Kang, Daolin Tang, Herbert J Zeh, Xin Chen, Daniel J Klionsky, Xiaoyan WangAbstract:Macroautophagy (hereafter referred to as "autophagy") is a lysosome-mediated degradation process that plays a complex role in cellular stress, either promoting survival or triggering death. Early studies suggest that Ferroptosis, an iron-dependent form of regulated cell death, is not related to autophagy. Conversely, recent evidence indicates that the molecular machinery of autophagy facilitates Ferroptosis through the selective degradation of anti-Ferroptosis regulators. However, the mechanism of autophagy-dependent Ferroptosis remains incompletely understood. Here, we examine the early dynamic change in protein expression of autophagic (e.g., MAP1LC3B and SQSTM1) or ferroptotic (e.g., SLC7A11 and GPX4) regulators in 60 human cancer cell lines in response to two classical Ferroptosis activators (erastin and RSL3) in the absence or presence of the lysosomal inhibitor chloroquine. Compared to erastin, RSL3 exhibits wider and stronger activity in the upregulation of MAP1LC3B-II or downregulation of SQSTM1 in 80% (48/60) or 63% (38/60) of cell lines, respectively. Both RSL3 and erastin failed to affect SLC7A11 expression, but they led to GPX4 downregulation in 12% (7/60) and 3% (2/60) of cell lines, respectively. Additionally, the intracellular iron exporter SLC40A1/ferroportin-1 was identified as a new substrate for autophagic elimination, and its degradation by SQSTM1 promoted Ferroptosis in vitro and in xenograft tumor mouse models. Together, these findings show tumor heterogeneity in autophagy-dependent Ferroptosis, which might have different biological behaviors with regard to the dynamic characteristics of cell death.
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clockophagy is a novel selective autophagy process favoring Ferroptosis
Science Advances, 2019Co-Authors: Minghua Yang, Pan Chen, Rui Kang, Guido Kroemer, Daolin Tang, Michael T Lotze, Daniel J KlionskyAbstract:Ferroptosis is a form of nonapoptotic regulated cell death driven by iron-dependent lipid peroxidation. Autophagy involves a lysosomal degradation pathway that can either promote or impede cell death. A high level of autophagy has been associated with Ferroptosis, but the mechanisms underpinning this relationship are largely elusive. We characterize the contribution of autophagy to Ferroptosis in human cancer cell lines and mouse tumor models. We show that “clockophagy,” the selective degradation of the core circadian clock protein ARNTL by autophagy, is critical for Ferroptosis. We identify SQSTM1 as a cargo receptor responsible for autophagic ARNTL degradation. ARNTL inhibits Ferroptosis by repressing the transcription of Egln2, thus activating the prosurvival transcription factor HIF1A. Genetic or pharmacological interventions blocking ARNTL degradation or inhibiting EGLN2 activation diminished, whereas destabilizing HIF1A facilitated, ferroptotic tumor cell death. Thus, our findings reveal a new pathway, initiated by the autophagic removal of ARNTL, that facilitates Ferroptosis induction.
Brent R. Stockwell - One of the best experts on this subject based on the ideXlab platform.
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Ferroptosis mechanisms biology and role in disease
Nature Reviews Molecular Cell Biology, 2021Co-Authors: Xuejun Jiang, Brent R. Stockwell, Marcus ConradAbstract:The research field of Ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by Ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to Ferroptosis. As such, pharmacological modulation of Ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of Ferroptosis, the potential physiological functions of Ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of Ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future Ferroptosis research.
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iPLA2β-mediated lipid detoxification controls p53-driven Ferroptosis independent of GPX4
'Springer Science and Business Media LLC', 2021Co-Authors: Delin Chen, Xuejun Jiang, Bo Chu, Ning Kon, Xin Yang, Zhaoqi Liu, Ying Jin, Raul Rabadan, Brent R. StockwellAbstract:p53 is able to induce Ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2β suppresses p53-medated Ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical Ferroptosis regulator GPX4
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emerging mechanisms and disease relevance of Ferroptosis
Trends in Cell Biology, 2020Co-Authors: Brent R. Stockwell, Xuejun JiangAbstract:Cell death is an essential feature of development in multicellular organisms, a critical driver of degenerative diseases, and can be harnessed for treating some cancers. Understanding the mechanisms governing cell death is critical for addressing its role in disease. Similarly, metabolism is essential for normal energy and biomolecule production, and goes awry in many diseases. Metabolism and cell death are tightly linked in the phenomenon of Ferroptosis, a form of regulated cell death driven by peroxidation of phospholipids. Glutathione peroxidase 4 (GPX4) uses glutathione to protect cells from Ferroptosis by eliminating phospholipid peroxides. Recent data have revealed glutathione/GPX4-independent axes for suppressing Ferroptosis, and insight into the regulation of iron and mitochondria in Ferroptosis. Ferroptosis has recently been implicated in multiple diseases, and functions as a tumor suppression mechanism. Ferroptosis induction is a promising approach in treating several conditions, including neoplastic diseases. Here, we summarize these recent advances.
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intercellular interaction dictates cancer cell Ferroptosis via nf2 yap signalling
Nature, 2019Co-Authors: Brent R. Stockwell, Minghui Gao, Alexander M Minikes, Huijie Bian, Zhinan Chen, Xuejun JiangAbstract:Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage and cancer1,2. The enzyme glutathione peroxidase 4 (GPX4) is a central regulator of Ferroptosis, and protects cells by neutralizing lipid peroxides, which are by-products of cellular metabolism. The direct inhibition of GPX4, or indirect inhibition by depletion of its substrate glutathione or the building blocks of glutathione (such as cysteine), can trigger Ferroptosis3. Ferroptosis contributes to the antitumour function of several tumour suppressors such as p53, BAP1 and fumarase4–7. Counterintuitively, mesenchymal cancer cells—which are prone to metastasis, and often resistant to various treatments—are highly susceptible to Ferroptosis8,9. Here we show that Ferroptosis can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin suppress Ferroptosis by activating the intracellular NF2 (also known as merlin) and Hippo signalling pathway. Antagonizing this signalling axis allows the proto-oncogenic transcriptional co-activator YAP to promote Ferroptosis by upregulating several Ferroptosis modulators, including ACSL4 and TFRC. This finding provides mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to Ferroptosis8. Notably, a similar mechanism also modulates Ferroptosis in some non-epithelial cells. Finally, genetic inactivation of the tumour suppressor NF2, a frequent tumorigenic event in mesothelioma10,11, rendered cancer cells more sensitive to Ferroptosis in an orthotopic mouse model of malignant mesothelioma. Our results demonstrate the role of intercellular interactions and intracellular NF2–YAP signalling in dictating ferroptotic death, and also suggest that malignant mutations in NF2–YAP signalling could predict the responsiveness of cancer cells to future Ferroptosis-inducing therapies. Ferroptosis in cancer cells can be regulated by cadherin-mediated intercellular contacts, NF2–Hippo signalling, and activity of the YAP transcription co-activator.
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intercellular interaction dictates cancer cell Ferroptosis via nf2 yap signalling
Nature, 2019Co-Authors: Alexander M Minikes, Brent R. Stockwell, Minghui Gao, Huijie Bian, Zhinan Chen, Xuejun JiangAbstract:Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage and cancer1,2. The enzyme glutathione peroxidase 4 (GPX4) is a central regulator of Ferroptosis, and protects cells by neutralizing lipid peroxides, which are by-products of cellular metabolism. The direct inhibition of GPX4, or indirect inhibition by depletion of its substrate glutathione or the building blocks of glutathione (such as cysteine), can trigger Ferroptosis3. Ferroptosis contributes to the antitumour function of several tumour suppressors such as p53, BAP1 and fumarase4-7. Counterintuitively, mesenchymal cancer cells-which are prone to metastasis, and often resistant to various treatments-are highly susceptible to Ferroptosis8,9. Here we show that Ferroptosis can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin suppress Ferroptosis by activating the intracellular NF2 (also known as merlin) and Hippo signalling pathway. Antagonizing this signalling axis allows the proto-oncogenic transcriptional co-activator YAP to promote Ferroptosis by upregulating several Ferroptosis modulators, including ACSL4 and TFRC. This finding provides mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to Ferroptosis8. Notably, a similar mechanism also modulates Ferroptosis in some non-epithelial cells. Finally, genetic inactivation of the tumour suppressor NF2, a frequent tumorigenic event in mesothelioma10,11, rendered cancer cells more sensitive to Ferroptosis in an orthotopic mouse model of malignant mesothelioma. Our results demonstrate the role of intercellular interactions and intracellular NF2-YAP signalling in dictating ferroptotic death, and also suggest that malignant mutations in NF2-YAP signalling could predict the responsiveness of cancer cells to future Ferroptosis-inducing therapies.
Da Pang - One of the best experts on this subject based on the ideXlab platform.
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Ferritinophagy is required for the induction of Ferroptosis by the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells.
Cell death & disease, 2019Co-Authors: Shiyao Sui, Jian Zhang, Qin Wang, Peiyuan Wang, Da PangAbstract:(+)-JQ1 is an inhibitor of the tumor-driver bromodomain protein BRD4 and produces satisfactory effects because it efficiently increases apoptosis. Ferroptosis is an oxidative cell death program differing from apoptosis. Ferroptosis is characterized by high levels of iron and reactive oxygen species and has been confirmed to suppress tumor growth. In this study, BRD4 expression in cancer and its influence on the prognosis of cancer patients were analyzed using data from public databases. In addition, the effect of the BRD4 inhibitor (+)-JQ1 on Ferroptosis was investigated via a series of in vitro assays. A nude mouse model was used to evaluate the function of (+)-JQ1 in Ferroptosis in vivo. The potential mechanisms by which (+)-JQ1 regulates Ferroptosis were explored. The results showed that BRD4 expression levels were higher in cancer tissues than in normal tissues and were related to poor prognosis in cancer patients. Furthermore, Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces Ferroptosis via BRD4 inhibition. Moreover, the anticancer effect of (+)-JQ1 was enhanced by Ferroptosis inducers. Further studies confirmed that (+)-JQ1 induced Ferroptosis via ferritinophagy, which featured autophagy enhancement by (+)-JQ1 and increased iron levels. Subsequently, the reactive oxygen species levels were increased by iron via the Fenton reaction, leading to Ferroptosis. In addition, expression of the Ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 may regulate Ferroptosis by controlling the expression of Ferroptosis-associated genes regulated by BRD4. Finally, (+)-JQ1 regulated ferritinophagy and the expression of Ferroptosis-associated genes via epigenetic inhibition of BRD4 by suppressing the expression of the histone methyltransferase G9a or enhancing the expression of the histone deacetylase SIRT1. In summary, the BRD4 inhibitor (+)-JQ1 induces Ferroptosis via ferritinophagy or the regulation of Ferroptosis-associated genes through epigenetic repression of BRD4.
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ferritinophagy is required for the induction of Ferroptosis by the bromodomain protein brd4 inhibitor jq1 in cancer cells
Cell Death and Disease, 2019Co-Authors: Shiyao Sui, Jian Zhang, Qin Wang, Peiyuan Wang, Da PangAbstract:(+)-JQ1 is an inhibitor of the tumor-driver bromodomain protein BRD4 and produces satisfactory effects because it efficiently increases apoptosis. Ferroptosis is an oxidative cell death program differing from apoptosis. Ferroptosis is characterized by high levels of iron and reactive oxygen species and has been confirmed to suppress tumor growth. In this study, BRD4 expression in cancer and its influence on the prognosis of cancer patients were analyzed using data from public databases. In addition, the effect of the BRD4 inhibitor (+)-JQ1 on Ferroptosis was investigated via a series of in vitro assays. A nude mouse model was used to evaluate the function of (+)-JQ1 in Ferroptosis in vivo. The potential mechanisms by which (+)-JQ1 regulates Ferroptosis were explored. The results showed that BRD4 expression levels were higher in cancer tissues than in normal tissues and were related to poor prognosis in cancer patients. Furthermore, Ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces Ferroptosis via BRD4 inhibition. Moreover, the anticancer effect of (+)-JQ1 was enhanced by Ferroptosis inducers. Further studies confirmed that (+)-JQ1 induced Ferroptosis via ferritinophagy, which featured autophagy enhancement by (+)-JQ1 and increased iron levels. Subsequently, the reactive oxygen species levels were increased by iron via the Fenton reaction, leading to Ferroptosis. In addition, expression of the Ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 may regulate Ferroptosis by controlling the expression of Ferroptosis-associated genes regulated by BRD4. Finally, (+)-JQ1 regulated ferritinophagy and the expression of Ferroptosis-associated genes via epigenetic inhibition of BRD4 by suppressing the expression of the histone methyltransferase G9a or enhancing the expression of the histone deacetylase SIRT1. In summary, the BRD4 inhibitor (+)-JQ1 induces Ferroptosis via ferritinophagy or the regulation of Ferroptosis-associated genes through epigenetic repression of BRD4.
Yiqun Jiang - One of the best experts on this subject based on the ideXlab platform.
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egln1 c myc induced lymphoid specific helicase inhibits Ferroptosis through lipid metabolic gene expression changes
Theranostics, 2017Co-Authors: Yiqun Jiang, Chao Mao, Rui Yang, Bin Yan, Ying Shi, Xiaoli Liu, Weiwei Lai, Yating Liu, Xiang Wang, Desheng XiaoAbstract:Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying Ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit Ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and Ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits Ferroptosis, which can be exploited for the development of therapeutic strategies targeting Ferroptosis for the treatment of cancer.
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abstract 4317 egln1 c myc induced lymphoid specific helicase inhibits Ferroptosis through lipid metabolic gene expression changes
Cancer Research, 2017Co-Authors: Yongguang Tao, Shuang Liu, Yiqun JiangAbstract:Ferroptosis has emerged as a new form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms of Ferroptosis remain poorly defined. We demonstrate that Lymphoid-specific helicase (LSH), a DNA methylation modifier, interacts with WDR76 to inhibit Ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and Ferroptosis related genes SCD1 and FADS2. These effects are dependent on iron and lipid reactive oxygen species. We further show that EGLN1 and c-Myc directly activate LSH expression by inhibiting HIF-1α. Finally, we demonstrate that LSH functions as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis for a c-Myc/EGLN1-mediated induction of LSH expression to inhibit Ferroptosis, which can be exploited for the development of therapeutic agents to target Ferroptosis in cancer. Note: This abstract was not presented at the meeting. Citation Format: Yongguang Tao, Shuang Liu, Yiqun Jiang. EGLN1/c-Myc induced lymphoid-specific helicase inhibits Ferroptosis through lipid metabolic gene expression changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2017-4317
Xuejun Jiang - One of the best experts on this subject based on the ideXlab platform.
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Ferroptosis mechanisms biology and role in disease
Nature Reviews Molecular Cell Biology, 2021Co-Authors: Xuejun Jiang, Brent R. Stockwell, Marcus ConradAbstract:The research field of Ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by Ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to Ferroptosis. As such, pharmacological modulation of Ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of Ferroptosis, the potential physiological functions of Ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of Ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future Ferroptosis research.
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iPLA2β-mediated lipid detoxification controls p53-driven Ferroptosis independent of GPX4
'Springer Science and Business Media LLC', 2021Co-Authors: Delin Chen, Xuejun Jiang, Bo Chu, Ning Kon, Xin Yang, Zhaoqi Liu, Ying Jin, Raul Rabadan, Brent R. StockwellAbstract:p53 is able to induce Ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2β suppresses p53-medated Ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical Ferroptosis regulator GPX4
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oncogenic activation of pi3k akt mtor signaling suppresses Ferroptosis via srebp mediated lipogenesis
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Jiajun Zhu, Craig B Thompson, Xuejun JiangAbstract:Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers Ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to Ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the Ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized Ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored Ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with Ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with Ferroptosis induction shows therapeutic promise in preclinical models.
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emerging mechanisms and disease relevance of Ferroptosis
Trends in Cell Biology, 2020Co-Authors: Brent R. Stockwell, Xuejun JiangAbstract:Cell death is an essential feature of development in multicellular organisms, a critical driver of degenerative diseases, and can be harnessed for treating some cancers. Understanding the mechanisms governing cell death is critical for addressing its role in disease. Similarly, metabolism is essential for normal energy and biomolecule production, and goes awry in many diseases. Metabolism and cell death are tightly linked in the phenomenon of Ferroptosis, a form of regulated cell death driven by peroxidation of phospholipids. Glutathione peroxidase 4 (GPX4) uses glutathione to protect cells from Ferroptosis by eliminating phospholipid peroxides. Recent data have revealed glutathione/GPX4-independent axes for suppressing Ferroptosis, and insight into the regulation of iron and mitochondria in Ferroptosis. Ferroptosis has recently been implicated in multiple diseases, and functions as a tumor suppression mechanism. Ferroptosis induction is a promising approach in treating several conditions, including neoplastic diseases. Here, we summarize these recent advances.
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artemisinin compounds sensitize cancer cells to Ferroptosis by regulating iron homeostasis
Cell Death & Differentiation, 2020Co-Authors: Guoqing Chen, Fahad A Benthani, Deguang Liang, Zhaoxiang Bian, Xuejun JiangAbstract:The antimalarial drug artemisinin and its derivatives have been explored as potential anticancer agents, but their underlying mechanisms are controversial. In this study, we found that artemisinin compounds can sensitize cancer cells to Ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation. Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to Ferroptosis. Further, by associating with cellular free iron and thus stimulating the binding of iron-regulatory proteins (IRPs) with mRNA molecules containing iron-responsive element (IRE) sequences, DAT impinges on IRP/IRE-controlled iron homeostasis to further increase cellular free iron. Importantly, in both in vitro and a mouse xenograft model in which Ferroptosis was triggered in cancer cells by the inducible knockout of GPX4, we found that DAT can augment GPX4 inhibition-induced Ferroptosis in a cohort of cancer cells that are otherwise highly resistant to Ferroptosis. Collectively, artemisinin compounds can sensitize cells to Ferroptosis by regulating cellular iron homeostasis. Our findings can be exploited clinically to enhance the effect of future Ferroptosis-inducing cancer therapies.