Genetic Profiles of Ferroptosis in Malignant Brain Tumors and Off-Target Effects of Ferroptosis Induction

Dahlmanns, Marc; Yakubov, Eduard; Dahlmanns, Jana Katharina

doi:10.3389/fonc.2021.783067

Cited by 16 publications

(13 citation statements)

References 74 publications

(98 reference statements)

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“…Ferroptosis is a recently described iron-dependent form of PCD, differing from other PCD types such as apoptosis and necroptosis (37). The ferrDB database contains information on all genes linked to ferroptosis and provides the latest resources for research (21).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, an association between ferroptosis-related signatures and drug screening was found in liver cancer (66) and the potential of enhancing treatment efficacy by inducing ferroptosis has attracted attention. Although studies on glioma have focused on the use of ferroptosis to predict prognosis, none have investigated potential drugs (9,36,37). Here, we used GDSC1, GDSC2, iLINCS, and CLUE to identify molecules that might reverse the tumor signature, observing that patients with high FRG scores may benefit more from treatment with an RTK pathway inhibitor, either by direct inhibition of the RTK or indirect inhibition by targeting downstream effectors such as the PI3K or MAPK pathways (Figure 9).…”

Section: Discussionmentioning

confidence: 99%

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A Novel Prognostic Signature Based on Glioma Essential Ferroptosis-Related Genes Predicts Clinical Outcomes and Indicates Treatment in Glioma

Yun

Wang

et al. 2022

Front. Oncol.

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BackgroundFerroptosis is a form of programmed cell death (PCD) that has been implicated in cancer progression, although the specific mechanism is not known. Here, we used the latest DepMap release CRISPR data to identify the essential ferroptosis-related genes (FRGs) in glioma and their role in patient outcomes.MethodsRNA-seq and clinical information on glioma cases were obtained from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). FRGs were obtained from the FerrDb database. CRISPR-screened essential genes (CSEGs) in glioma cell lines were downloaded from the DepMap portal. A series of bioinformatic and machine learning approaches were combined to establish FRG signatures to predict overall survival (OS) in glioma patients. In addition, pathways analysis was used to identify the functional roles of FRGs. Somatic mutation, immune cell infiltration, and immune checkpoint gene expression were analyzed within the risk subgroups. Finally, compounds for reversing high-risk gene signatures were predicted using the GDSC and L1000 datasets.ResultsSeven FRGs (ISCU, NFS1, MTOR, EIF2S1, HSPA5, AURKA, RPL8) were included in the model and the model was found to have good prognostic value (p < 0.001) in both training and validation groups. The risk score was found to be an independent prognostic factor and the model had good efficacy. Subgroup analysis using clinical parameters demonstrated the general applicability of the model. The nomogram indicated that the model could effectively predict 12-, 36-, and 60-months OS and progression-free interval (PFI). The results showed the presence of more aggressive phenotypes (lower numbers of IDH mutations, higher numbers of EGFR and PTEN mutations, greater infiltration of immune suppressive cells, and higher expression of immune checkpoint inhibitors) in the high-risk group. The signaling pathways enriched closely related to the cell cycle and DNA damage repair. Drug predictions showed that patients with higher risk scores may benefit from treatment with RTK pathway inhibitors, including compounds that inhibit RTKs directly or indirectly by targeting downstream PI3K or MAPK pathways.ConclusionIn summary, the proposed cancer essential FRG signature predicts survival and treatment response in glioma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Novel Prognostic Signature Based on Glioma Essential Ferroptosis-Related Genes Predicts Clinical Outcomes and Indicates Treatment in Glioma

Yun

Wang

et al. 2022

Front. Oncol.

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“…Experimental studies have shown that the efficacy of temozolomide can be improved by inducing ferroptosis. Ferroptosis can also be activated to improve the treatment of the malignant stages of neuroblastoma, meningioma, and glioma [68]. Despite their positive effects during chemotherapy, drugs used to induce ferroptosis (e.g., sorafenib) and genetic manipulation of key participants in ferroptosis (e.g., cystine-glutamate exchanger xCT and GPX4) also affect neuronal function and cognitive ability.…”

Section: Brain Tumorsmentioning

confidence: 99%

Emerging Mechanisms and Targeted Therapy of Ferroptosis in Neurological Diseases and Neuro-oncology

Wang¹,

Tang²,

Zhu³

et al. 2022

Int. J. Biol. Sci.

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Ferroptosis is a novel type of cell death characterized by iron-dependent lipid peroxidation that involves a variety of biological processes, such as iron metabolism, lipid metabolism, and oxidative stress. A growing body of research suggests that ferroptosis is associated with cancer and neurodegenerative diseases, such as glioblastoma, Alzheimer's disease, Parkinson's disease, and stroke. Building on these findings, we can selectively induce ferroptosis for the treatment of certain cancers, or we can treat neurodegenerative diseases by inhibiting ferroptosis. This review summarizes the relevant advances in ferroptosis, the regulatory mechanisms of ferroptosis, the participation of ferroptosis in brain tumors and neurodegenerative diseases, and the corresponding drug therapies to provide new potential targets for its treatment.

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“…However, grade II and III meningiomas result in poor prognosis [ 3 ]. To date, many chemotherapeutic drugs and hormone therapies have been used to treat meningiomas, but with only modest benefits, such as gold standard drug treatment with the chemotherapeutic drug temozolomide, which only slightly improved survival [ 4 , 5 ]. Therefore, exploring the pathogenesis of meningioma may contribute to the development of new targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have shown that MEF2C silencing downregulates NF2 and E-cadherin and enhances ferroptosis in meningiomas, suggesting that NF2 loss or low E-cadherin expression predisposes meningiomas to ferroptosis [ 14 ]. In addition, experimental studies have shown that temozolomide's efficacy against neuroblastoma, meningioma, and glioma can be improved by inducing ferroptosis [ 5 ]. However, there are few reports on the specific mechanism of ferroptosis in meningioma and the development of drugs to induce ferroptosis; thus, further exploration is needed.…”

Section: Introductionmentioning

confidence: 99%

miR-127-5p Targets JAM3 to Regulate Ferroptosis, Proliferation, and Metastasis in Malignant Meningioma Cells

2022

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Objective. Meningiomas are one of the most common primary tumors of the central nervous system. Most of them are benign and can be cured by surgery, while a few meningiomas are malignant. Ferroptosis gene characteristics might be associated with drug therapy and survival in patients with clinically aggressive, unresectable meningiomas. This study explored the mechanism of differentially expressed miRNAs and ferroptosis in meningioma to provide a new reference to treat meningioma. Methods. Bioinformatics analysis of differential miRNA profiles and functions in patients with meningioma was performed. The contents of lactate dehydrogenase (LDH), malondialdehyde (MDA), and Fe2+ were determined. Reactive oxygen species (ROS) values, as well as cell cycle changes, were analyzed by flow cytometry. The targets of miR-127-5p and JAM3 were detected by dual luciferase assays. Cell counting kit-8 (CCK8) and Transwell assays were used to analyze cell activity. Ki67 expression was analyzed by immunohistochemistry. Expression levels of miR-127-5p and JAM3 were analyzed by RT-qPCR. GPX4 expression was quantified by western blotting. Results. miR-127-5p was expressed at low levels in IOMM-Lee cells, while JAM3 was highly expressed in IOMM-Lee cells. A dual luciferase assay demonstrated that miR-127-5p could target JAM3. Upregulation of miR-127-5p in IOMM-Lee cells resulted in cell cycle arrest and inhibition of cell activity. Upregulation of miR-127-5p increased LDH, MDA, and ROS levels and Fe2+ content and inhibited the expression of GPX4 protein. Upregulation of JAM3 reversed the results of miR-127-5p upregulation. Conclusion. miR-127-5p regulated meningioma formation and ferroptosis through JAM3, providing insights for the development of new treatments for meningioma.

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Genetic Profiles of Ferroptosis in Malignant Brain Tumors and Off-Target Effects of Ferroptosis Induction

Cited by 16 publications

References 74 publications

A Novel Prognostic Signature Based on Glioma Essential Ferroptosis-Related Genes Predicts Clinical Outcomes and Indicates Treatment in Glioma

A Novel Prognostic Signature Based on Glioma Essential Ferroptosis-Related Genes Predicts Clinical Outcomes and Indicates Treatment in Glioma

Emerging Mechanisms and Targeted Therapy of Ferroptosis in Neurological Diseases and Neuro-oncology

miR-127-5p Targets JAM3 to Regulate Ferroptosis, Proliferation, and Metastasis in Malignant Meningioma Cells

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