System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Авг. 29, 2022

The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis an iron-mediated form cell death caused by the accumulation lipid peroxides. intracellular imbalance between oxidant and antioxidant due abnormal expression multiple redox active enzymes will promote produce reactive oxygen species (ROS). So far, few pathways regulators have been discovered regulate ferroptosis. In particular, cystine/glutamate antiporter (System X c − ), glutathione peroxidase 4 (GPX4) (GSH) /GSH/GPX4 axis) plays key role in preventing peroxidation-mediated ferroptosis, because which could be inhibited blocking System axis. This review aims present current understanding mechanism based on axis treatment

Язык: Английский

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Insights into N6-methyladenosine and programmed cell death in cancer

Molecular Cancer, Год журнала: 2022, Номер 21(1)

Опубликована: Янв. 28, 2022

Abstract N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic recent years. M6A plays multifunctional roles normal abnormal biological processes, its role may vary greatly depending on position m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis ferroptosis, which involve breakdown plasma membrane. Based implications methylation PCD, regulators functional were comprehensively studied reported. In this review, we focus high-complexity links between different types PCD pathways, are then closely associated with initiation, progression resistance cancer. Herein, clarifying relationship is great significance to provide novel strategies for cancer treatment, potential prospect clinical application.

Язык: Английский

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Role of m6A writers, erasers and readers in cancer

Experimental Hematology and Oncology, Год журнала: 2022, Номер 11(1)

Опубликована: Авг. 9, 2022

Abstract The N(6)-methyladenosine (m6A) modification is the most pervasive of human RNAs. In recent years, an increasing number studies have suggested that m6A likely plays important roles in cancers. Many demonstrated involved biological functions cancer cells, such as proliferation, invasion, metastasis, and drug resistance. addition, closely related to prognosis patients. this review, we highlight advances understanding function various We emphasize importance progression look forward describe future research directions.

Язык: Английский

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Essential roles of exosome and circRNA_101093 on ferroptosis desensitization in lung adenocarcinoma

Cancer Communications, Год журнала: 2022, Номер 42(4), С. 287 - 313

Опубликована: Фев. 20, 2022

Resistance to ferroptosis, a regulated cell death caused by iron-dependent excessive accumulation of lipid peroxides, has recently been linked lung adenocarcinoma (LUAD). Intracellular antioxidant systems are required for protection against ferroptosis. The purpose the present study was investigate whether and how extracellular system desensitizes LUAD cells ferroptosis.Established human fibroblasts MRC-5, WI38, H1650, PC9, H1975, H358, A549, H1299 lines, tumor matched normal adjacent tissues LUAD, plasma from healthy individuals patients were used in this study. Immunohistochemistry immunoblotting analyze protein expression, quantitative reverse transcription-PCR mRNA expression. Cell viability, death, reactive oxygen species generation measured evaluate responses Exosomes observed using transmission electron microscope. localization arachidonic acid (AA) detected click chemistry labeling followed confocal microscopy. Interactions between RNAs proteins RNA pull-down, immunoprecipitation photoactivatable ribonucleoside-enhanced crosslinking methods. Proteomic analysis RNA-regulated proteins, metabolomic performed metabolites. Cell-derived xenograft, patient-derived cell-implanted intrapulmonary mouse models plasma/tissue specimens validate molecular mechanism.Plasma exosome specifically reduced peroxidation desensitized A potential explanation is that exosomal circRNA_101093 (cir93) maintained an elevation intracellular cir93 modulate AA, poly-unsaturated fatty critical ferroptosis-associated increased membrane. Mechanistically, interacted with acid-binding 3 (FABP3), which transported AA facilitated its reaction taurine. Thus, global reduced, whereas N-arachidonoyl taurine (NAT, product taurine) induced. Notably, role NAT suppressing incorporation into membrane also revealed. In pre-clinical vivo models, reducing improved ferroptosis-based treatment.Exosome essential desensitizing blocking may be helpful future treatment.

Язык: Английский

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RNA Modifications and Epigenetics in Modulation of Lung Cancer and Pulmonary Diseases

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(19), С. 10592 - 10592

Опубликована: Сен. 30, 2021

Lung cancer is the leading cause of cancer-related mortality worldwide, and its tumorigenesis involves accumulation genetic epigenetic events in respiratory epithelium. Epigenetic modifications, such as DNA methylation, RNA modification, histone have been widely reported to play an important role lung development other pulmonary diseases. Whereas functionality chromatin modifications referred epigenetics characterized, various nucleotides recently come into prominence functionally important. N6-methyladosine (m6A) most prevalent internal modification mRNAs, machinery writers, erasers, readers well-characterized. However, several nucleotide mRNAs noncoding RNAs also shown regulation biological processes pathology. Such epitranscriptomic regulating aspects metabolism, including transcription, translation, splicing, stability. The dysregulation has implicated pathological associated with carcinogenesis uncontrolled cell proliferation, migration, invasion, epithelial-mesenchymal transition. In recent years, advancement sequencing technology, high-resolution maps different tissues, organs, or disease models are being constantly at a dramatic speed. This facilitates further understanding relationship between epitranscriptomics, shedding light on new therapeutic possibilities. this review, we summarize basic information m6A, m1A, m5C, m7G, pseudouridine, A-to-I editing. We then demonstrate their relation kinds diseases, especially cancer. By comparing roles review may provide some insights offer better involvement

Язык: Английский

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Ferroptosis in Cancer Progression: Role of Noncoding RNAs

International Journal of Biological Sciences, Год журнала: 2022, Номер 18(5), С. 1829 - 1843

Опубликована: Янв. 1, 2022

Ferroptosis is a novel form of programmed cell death, and it characterized by iron-dependent oxidative damage, lipid peroxidation reactive oxygen species accumulation. Notable studies have revealed that ferroptosis plays vital roles in tumor occurrence abundant cells can inhibit progression. Recently, some noncoding RNAs (ncRNAs), particularly microRNAs, long RNAs, circular been shown to be involved biological processes ferroptosis, thus affecting cancer growth. However, the definite regulatory mechanism this phenomenon still unclear. To clarify issue, increasing focused on ncRNAs initiation development role progression various cancers, such as lung, liver, breast cancers. In review, we systematically summarized relationship between ferroptosis-associated Moreover, additional evidence needed identify ferroptosis-related This review will help us understand may provide new ideas for exploring diagnostic therapeutic biomarkers future.

Язык: Английский

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RNA binding protein NKAP protects glioblastoma cells from ferroptosis by promoting SLC7A11 mRNA splicing in an m6A-dependent manner

Cell Death and Disease, Год журнала: 2022, Номер 13(1)

Опубликована: Янв. 21, 2022

Abstract Ferroptosis is a form of cell death characterized by lipid peroxidation. Previous studies have reported that knockout NF-κB activating protein (NKAP), an RNA-binding protein, increased peroxidation level in naive T cells and induced colon cancer cells. However, there was no literature the relationship between NKAP ferroptosis glioblastoma Notably, mechanism modulating still unknown. Here, we found knockdown Silencing sensitivity to inducers both vitro vivo. Exogenous overexpression promoted resistance positively regulating defense namely cystine/glutamate antiporter (SLC7A11). The regulation SLC7A11 can be weakened m 6 A methylation inhibitor cycloleucine writer METTL3. combined “RGAC” motif which exactly line with “RGACH” (R = A/G, H A/U/C) uncovered A-sequence. RNA Immunoprecipitation (RIP) Co-Immunoprecipitation (Co-IP) proved interaction on transcript. Following its binding A, recruited splicing factor proline glutamine-rich (SFPQ) recognize splice site then conducted transcription termination (TTS) event transcript retention last exon, screened RNA-sequence Mass Spectrometry (MS). In conclusion, acted as new suppressor promoting mRNA maturation.

Язык: Английский

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Regulatory pathways and drugs associated with ferroptosis in tumors

Cell Death and Disease, Год журнала: 2022, Номер 13(6)

Опубликована: Июнь 10, 2022

Abstract Ferroptosis is a type of cell death that depends on iron and reactive oxygen species (ROS). The accumulation lipid peroxidation primarily initiates oxidative membrane damage during ferroptosis. core molecular mechanism ferroptosis includes the regulation oxidation balance between antioxidant defense. Tumor cells usually contain large amount H 2 O , ferrous/iron ions will react with excessive in to produce hydroxyl radicals induce tumor cells. Here, we reviewed latest studies introduced tumor-related signaling pathways We paid particular attention role noncoding RNA, nanomaterials, drugs, targeted treatment using drugs for mediating process Finally, discussed currently unresolved problems future research directions prospects this emerging field. Therefore, have attempted provide reference further understanding pathogenesis proposed new targets cancer treatment.

Язык: Английский

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HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1

Cell Reports, Год журнала: 2023, Номер 42(8), С. 112945 - 112945

Опубликована: Авг. 1, 2023

Solid tumors have developed robust ferroptosis resistance. The mechanism underlying resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which under hypoxia, HIF-1α is main driver of hypoxia-induced Mechanistically, HIF-1α-induced lactate contributes to pH-dependent manner parallel classical SLC7A11 and FSP1 systems. addition, also enhances transcription SLC1A1, an important glutamate transporter, cystine uptake promote support role hypoxia resistance, silencing sensitizes mouse inducers. conclusion, our results reveal by drives identify alleviation induction as promising therapeutic strategy for tumors.

Язык: Английский

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Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Дек. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Язык: Английский

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