Dataset Information

Synchronous Disintegration of Ferroptosis Defense Axis via Engineered Exosome-Conjugated Magnetic Nanoparticles for Glioblastoma Therapy.

ABSTRACT: Glioblastoma (GBM) is one of the most fatal central nervous system tumors and lacks effective or sufficient therapies. Ferroptosis is a newly discovered method of programmed cell death and opens a new direction for GBM treatment. However, poor blood-brain barrier (BBB) penetration, reduced tumor targeting ability, and potential compensatory mechanisms hinder the effectiveness of ferroptosis agents during GBM treatment. Here, a novel composite therapeutic platform combining the magnetic targeting features and drug delivery properties of magnetic nanoparticles with the BBB penetration abilities and siRNA encapsulation properties of engineered exosomes for GBM therapy is presented. This platform can be enriched in the brain under local magnetic localization and angiopep-2 peptide-modified engineered exosomes can trigger transcytosis, allowing the particles to cross the BBB and target GBM cells by recognizing the LRP-1 receptor. Synergistic ferroptosis therapy of GBM is achieved by the combined triple actions of the disintegration of dihydroorotate dehydrogenase and the glutathione peroxidase 4 ferroptosis defense axis with Fe₃ O₄ nanoparticle-mediated Fe²⁺ release. Thus, the present findings show that this system can serve as a promising platform for the treatment of glioblastoma.

SUBMITTER: Li B

PROVIDER: S-EPMC9189685 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Synchronous Disintegration of Ferroptosis Defense Axis via Engineered Exosome-Conjugated Magnetic Nanoparticles for Glioblastoma Therapy.

Li Boyan B Chen Xin X Qiu Wei W Zhao Rongrong R Duan Jiazhi J Zhang Shouji S Pan Ziwen Z Zhao Shulin S Guo Qindong Q Qi Yanhua Y Wang Wenhan W Deng Lin L Ni Shilei S Sang Yuanhua Y Xue Hao H Liu Hong H Li Gang G

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220504 17

Glioblastoma (GBM) is one of the most fatal central nervous system tumors and lacks effective or sufficient therapies. Ferroptosis is a newly discovered method of programmed cell death and opens a new direction for GBM treatment. However, poor blood-brain barrier (BBB) penetration, reduced tumor targeting ability, and potential compensatory mechanisms hinder the effectiveness of ferroptosis agents during GBM treatment. Here, a novel composite therapeutic platform combining the magnetic targeting ...[more]

PMID: 35508804

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Project description:BackgroundGlioblastoma multiforme (GBM)is a highly aggressive malignancy of the central nervous system characterized by poor survival rates. Ferroptosis, an iron-dependent cell death pathway, is a promising therapeutic target for GBM. However, current treatments targeting cell death pathways have not yielded expected results. Long noncoding RNAs (lncRNAs) have been implicated in tumour proliferation, however, their role in ferroptosis in GBM remains underexplored. This study investigated the interplay between the lncRNA LINC01088 and ferroptosis in GBM to identify novel therapeutic strategies.MethodsWe conducted gain- and loss-of-function studies to assess the impact of LINC01088 on GBM tumourigenesis and ferroptosis both in vitro and in vivo. Bioinformatics, dual-luciferase reporter assays, chromatin immunoprecipitation, RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), and transcriptome sequencing were utilized to elucidate the mechanisms underlying LINC01088 expression and its downstream effects on ferroptosis.ResultsThe transcription factor specificity protein 1 (SP1) was identified as the promoter of LINC01088 transcription, which facilitated GBM progression. LINC01088 was found to inhibit ferroptosis and promote malignancy. Mechanistically, LINC01088 stabilized HLTF by enhancing its interaction with USP7 and preventing ubiquitin-mediated degradation. The stabilization of HLTF led to the upregulation of SLC7A11, which inhibits ferroptosis in GBM. Rescue experiments confirmed that altering HLTF levels reversed the ferroptotic phenotypes associated with LINC01088 modulation.ConclusionThis study revealed a novel SP1/LINC01088/HLTF/USP7/SLC7A11 axis that regulates ferroptosis in GBM, highlighting LINC01088 as a potential therapeutic target for ferroptosis-dependent GBM treatment.Key pointsLINC01088 is transcriptionally upregulated by SP1. LINC01088 acts as a scaffold platform to bind USP7 and HLTF. USP7, as a deubiquitinating enzyme of HLTF, participates in inhibiting the ubiquitin-proteasome degradation of HLTF. HLTF transcriptionally upregates the expression of downstream SLC7A11, and ferroptosis of GBM cells was inhibited.

Project description:Background Our previous study has identified a novel circRNA (circDIDO1) that is down-regulated in gastric cancer (GC) and significantly inhibits GC progression. The purpose of this study is to identify the molecular mechanism for circDIDO1 and to evaluate the therapeutic effect of circDIDO1 in GC. Methods By combining bioinformatic analysis with RNA sequencing data, we predicted the potential target of circDIDO1 and further validated the regulatory mechanisms for its tumor suppressor function in GC. RIP assay, luciferase reporter assay and in vitro cell function assays were performed to analyze circDIDO1-regulated downstream target genes. For the therapeutic study, circDIDO1-loaded, RGD-modified exosomes (RGD-Exo-circDIDO1) were constructed and its anti-tumor efficacy and biological safety were evaluated in vitro and in vivo. Results CircDIDO1 inhibited GC progression by regulating the expression of the signal transducer inhibitor SOSC2 through sponging miR-1307-3p. Overexpression of circDIDO1 or SOSC2 antagonized the oncogenic role of miR-1307-3p. RGD-Exo-circDIDO1 could efficiently deliver circDIDO1 to increase SOCS2 expression in GC cells. Compared with PBS and RGD-Exo-vector treatment, RGD-Exo-circDIDO1 treatment significantly inhibited the proliferation, migration and invasion of GC cells while promoted cell apoptosis. The therapeutic efficacy of RGD-Exo-circDIDO1 was further confirmed in a mouse xenograft tumor model. In addition, major tissues including the heart, liver, spleen, lungs and kidneys showed no obvious histopathological abnormalities or lesions in the RGD-Exo-circDIDO1 treated group. Conclusion Our findings revealed that circDIDO1 suppressed the progression of GC via modulating the miR-1307-3p/SOSC2 axis. Systemic administration of RGD modified, circDIDO1 loaded exosomes repressed the tumorigenicity and aggressiveness of GC both in vitro and in vivo, suggesting that RGD-Exo-circDIDO1 could be used as a feasible nanomedicine for GC therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03527-z.

Project description:BackgroundGlioma exhibit heterogeneous susceptibility for targeted ferroptosis. How circRNAs alterations in glioma promote iron metabolism and ferroptosis defense remains unclarified.MethodsThe highly enriched circRNAs in glioblastoma (GBM) were obtained through analysis of sequencing datasets. Quantitative real-time PCR (qRT-PCR) was used to determine the expression of circRNF10 in glioma and normal brain tissue. Both gain-of-function and loss-of-function studies were used to assess the effects of circRNF10 on ferroptosis using in vitro and in vivo assays. The hypothesis that ZBTB48 promotes ferroptosis defense was established using bioinformatics analysis and functional assays. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between circRNF10 and target proteins including ZBTB48, MKRN3 and IGF2BP3. The posttranslational modification mechanism of ZBTB48 was verified using coimmunoprecipitation (co-IP) and ubiquitination assays. The transcription activation of HSPB1 and IGF2BP3 by ZBTB48 was confirmed through luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays. The stabilizing effect of IGF2BP3 on circRNF10 was explored by actinomycin D assay. Finally, a series of in vivo experiments were performed to explore the influences of circRNF10 on the glioma progression.ResultsA novel circular RNA, hsa_circ_0028912 (named circRNF10), which is significantly upregulated in glioblastoma tissues and correlated with patients' poor prognosis. Through integrated analysis of the circRNA-proteins interaction datasets and sequencing results, we reveal ZBTB48 as a transcriptional factor binding with circRNF10, notably promoting upregulation of HSPB1 and IGF2BP3 expression to remodel iron metabolism and facilitates the launch of a circRNF10/ZBTB48/IGF2BP3 positive feedback loop in GSCs. Additionally, circRNF10 can competitively bind to MKRN3 and block E3 ubiquitin ligase activity to enhance ZBTB48 expression. Consequently, circRNF10-overexpressed glioma stem cells (GSCs) display lower Fe2+ accumulation, selectively priming tumors for ferroptosis evading.ConclusionOur research presents abnormal circRNAs expression causing a molecular and metabolic change of glioma, which we leverage to discover a therapeutically exploitable vulnerability to target ferroptosis.

Dataset Information

Synchronous Disintegration of Ferroptosis Defense Axis via Engineered Exosome-Conjugated Magnetic Nanoparticles for Glioblastoma Therapy.

Publications

Synchronous Disintegration of Ferroptosis Defense Axis via Engineered Exosome-Conjugated Magnetic Nanoparticles for Glioblastoma Therapy.

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