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Since the migrasome concept was first proposed in 2015, extensive research has been conducted on these novel organelles, which grow on retracted fibers at the posterior end of migrating cells. Recently, molecular markers, biological functions, and clinical values based on the initial formation mechanism of migrasomes have emerged. Additionally, researchers are recognizing the significant role that migrasomes play in the pathological and diagnostic processes of clinical diseases. In this review, we summarize recent advances in the biology and clinical application of migrasomes and provide a comprehensive view of the prospective challenges surrounding their clinical application.
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Movimiento Celular , Orgánulos , Humanos , Orgánulos/metabolismo , AnimalesRESUMEN
BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive human cancers and has poor prognosis. Approximately 80% of TNBC cases belong to the molecular basal-like subtype, which can be exploited therapeutically by inducing differentiation. However, the strategies for inducing the differentiation of TNBC remain underexplored. METHODS: A three-dimensional (3D) morphological screening model based on a natural compound library was used to identify possible candidate compounds that can induce TNBC cell differentiation. The efficacy of rutaecarpine was verified using assays: RT-qPCR, RNA-seq, flow cytometry, immunofluorescence, SCENITH and label-free LC-MS/MS. The direct targets of rutaecarpine were identified through drug affinity responsive target stability (DARTS) assay. A xenograft mice model was also constructed to confirm the effect of rutaecarpine in vivo. RESULTS: We identified that rutaecarpine, an indolopyridoquinazolinone, induces luminal differentiation of basal TNBC cells in both 3D spheroids and in vivo mice models. Mechanistically, rutaecarpine treatment leads to global metabolic stress and elevated ROS in 3D cultured TNBC cells. Moreover, NAC, a scavenger of ROS, impedes rutaecarpine-induced differentiation of TNBC cells in 3D culture. Finally, we identified fumarate hydratase (FH) as the direct interacting target of rutaecarpine. The inhibition of FH and the knockdown of FH consistently induced the differentiation of TNBC cells in 3D culture. CONCLUSIONS: Our results provide a platform for differentiation therapy drug discovery using 3D culture models and identify rutaecarpine as a potential compound for TNBC treatment.
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Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Fumarato Hidratasa , Cromatografía Liquida , Especies Reactivas de Oxígeno , Espectrometría de Masas en Tándem , Diferenciación Celular , Modelos Animales de EnfermedadRESUMEN
Immunogenic cell death (ICD), one of cell-death types through release of damage-associated molecular patterns from dying tumor cells, activates tumor-specific immune response and elicits anti-tumor immunity by traditional radiotherapy and chemotherapy. However, whether natural products could induce ICD in leukemia is not elucidated. Here, we report dietary γ-mangostin eradicates murine primary leukemic cells and prolongs the survival of leukemic mice. As well, it restrains primary leukemic cells and CD34+ leukemic progenitor cells from leukemia patients. Strikingly, γ-mangostin attenuates leukemic cells by inducing ICD as characterized by expression of HSP90B1, ANXA1 and IL1B. Additionally, γ-mangostin accelerates cytoplasmic chromatin fragments generation, promoting DNA damage response, and enhances cGAS activation, leading to up-regulation of chemokines. Meanwhile, it induces HDAC4 degradation and acetylated histone H3 accumulation, which promotes chemokines transcription. Ultimately, CD8+ T cell is activated and recruited by γ-mangostin-induced chemokines in the microenvironment. Our study identifies γ-mangostin triggers ICD and activates cGAS signaling through DNA damage response and epigenetic modification. Therefore, dietary γ-mangostin would act as a potential agent to provoke anti-tumor immunity in the prevention and treatment of leukemia.
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Muerte Celular Inmunogénica , Leucemia Mieloide Aguda , Humanos , Animales , Ratones , Leucemia Mieloide Aguda/tratamiento farmacológico , Dieta , Quimiocinas , Microambiente TumoralRESUMEN
The correct duplication and transfer of genetic material to daughter cells is the major event of cell division. Dysfunction of DNA replication or chromosome segregation presents challenges in cancer initiation and development as well as opportunities for cancer treatment. Cyclic GMP-AMP synthase (cGAS) of the innate immune system detects cytoplasmic DNA and mediates downstream immune responses through the molecule stimulator of interferon genes (STING). However, how cytosolic DNA sensor cGAS participates in guaranteeing accurate cell division and preventing tumorigenesis is still unclear. Recent evidence indicates malfunction of cGAS/STING pathway in cancer progression. Cell cycle-targeted therapy synergizes with immunotherapy via cGAS/STING activation, leading to promising therapeutic benefit. Here, we review the interactions between cell cycle regulation and cGAS/STING signaling, thus enabling us to understand the role of cGAS/STING in cancer initiation, development, and treatment.
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Proteínas de la Membrana , Neoplasias , Ciclo Celular/genética , División Celular , ADN/metabolismo , Humanos , Inmunidad Innata , Inmunoterapia , Proteínas de la Membrana/metabolismo , Neoplasias/genética , Neoplasias/terapia , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismoRESUMEN
Single-pixel imaging enjoys advantages of low budget, broad spectrum, and high imaging speed. However, existing methods cannot clearly reconstruct the object that is fast rotating or randomly moving. In this work, we put forward an effective method to image a randomly moving object based on geometric moment analysis. To the best of our knowledge, this is the first work that reconstructs the shape and motion state of the target without prior knowledge of the speed or position. By using the cake-cutting order Hadamard illumination patterns and low-order geometric moment patterns, we obtain a high-quality video stream of the target which moves at high and varying translational and rotational speeds. The efficient method as verified by simulation and experimental results has great potential for practical applications such as Brownian motion microscopy and remote sensing.
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Morphological rearrangement of the endoplasmic reticulum (ER) is critical for metazoan mitosis. Yet, how the ER is remodeled by the mitotic signaling remains unclear. Here, we report that mitotic Aurora kinase A (AURKA) employs a small GTPase, Rab1A, to direct ER remodeling. During mitosis, AURKA phosphorylates Rab1A at Thr75. Structural analysis demonstrates that Thr75 phosphorylation renders Rab1A in a constantly active state by preventing interaction with GDP-dissociation inhibitor (GDI). Activated Rab1A is retained on the ER and induces the oligomerization of ER-shaping protein RTNs and REEPs, eventually triggering an increase of ER complexity. In various models, from Caenorhabditis elegans and Drosophila to mammals, inhibition of Rab1AThr75 phosphorylation by genetic modifications disrupts ER remodeling. Thus, our study reveals an evolutionarily conserved mechanism explaining how mitotic kinase controls ER remodeling and uncovers a critical function of Rab GTPases in metaphase.
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Aurora Quinasa A , Mitosis , Animales , Fosforilación , Aurora Quinasa A/metabolismo , Transducción de Señal , Retículo Endoplásmico/metabolismo , Mamíferos/metabolismoRESUMEN
SOX1, a well-known tumor suppressor, delays malignant progression in most cancer types. However, high expression of SOX1 in late-stage head and neck squamous cell carcinoma leads to poor prognosis. In this study, we show that SOX1 induces nasopharyngeal carcinoma (NPC) cells to enter a quiescent state. Using a model that mimics therapeutic resistance and tumor recurrence, a subpopulation of SOX1-induced NPC cells is refractory to paclitaxel, a cell cycle-specific chemotherapy drug. These cells maintain a quiescent state with decreased translational activity and down-regulated cell growth potential. However, once SOX1 expression is decreased, the NPC cells recover and enter a proliferative state. The chemotherapy resistance induced by SOX1 can not pass to next generation, as the cells that undergo re-proliferation become sensitive to paclitaxel again. Moreover, SOX1 directly binds to the promoter region of the MYC gene, leading to transcriptional suppression. When switching to a paclitaxel-free culture environment, the cells with decreased levels of SOX1 re-express MYC, resulting in increased abundance of proliferative cancer cells. Our study presents an evolutionary trade-off between tumor growth and chemoresistance orchestrated by SOX1-MYC in NPC. Basing on the dynamic role of SOX1 in different stages of cancer development, SOX1 would be regarded as a "tumor hypnotist".
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OBJECTIVES: Mutant C/EBPα p30 (mp30), the product of C/EBPα double mutations (DM), lacks transactivation domain 1 and has C-terminal loss-of-function mutation. Acute myeloid leukaemia (AML) patients harbouring C/EBPα DM could be classified as a distinct subgroup with favourable prognosis. However, the underlying mechanism remains elusive. MATERIALS AND METHODS: Autophagy regulated by mp30 was detected by western blot and immunofluorescence. Immune infiltration analysis and GSEA were performed to investigate autophagic and inflammatory status of AML patients from the GSE14468 cohort. Flow cytometry was applied to analyse T cell activation. RESULTS: Mp30 inhibited autophagy by suppressing nucleus translocation of NF-κB. Autophagy-associated secretion of IL-1ß was decreased in mp30-overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8+ T cell infiltration was upregulated in C/EBPα DM AML patients. Consistently, the proportion of CD8+ CD69+ T cells in peripheral blood mononuclear cells (PBMCs) was upregulated after co-culture with mp30 AML cell conditional culture medium. Knock-out of IL-1ß in AML cells also enhanced CD8+ T cell activation. Accordingly, IL-1ß expression was significantly reduced in the bone marrow (BM) cells of C/EBPα DM AML patients compared to the wildtype, while the CD8+ CD69+ T cell proportion was specifically elevated. CONCLUSIONS: C/EBPα DM alleviates immunosuppression of CD8+ T cells by inhibiting the autophagy-associated secretion of IL-1ß, which elucidated that repression of autophagy-related inflammatory response in AML patients might achieve a favourable clinical benefit.
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Proteína alfa Potenciadora de Unión a CCAAT , Leucemia Mieloide Aguda , Humanos , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Linfocitos T CD8-positivos/metabolismo , Leucocitos Mononucleares/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Autofagia , Terapia de InmunosupresiónRESUMEN
Uncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.
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Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Mitosis , Fosforilación Oxidativa , Adenosina Trifosfato/metabolismo , Animales , Aurora Quinasa A/metabolismo , Azepinas/farmacología , Neoplasias de la Mama/patología , Sistemas CRISPR-Cas/genética , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Citosol/metabolismo , Sinergismo Farmacológico , Metabolismo Energético/efectos de los fármacos , Femenino , Homeostasis/efectos de los fármacos , Humanos , Metformina/farmacología , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitosis/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Pirimidinas/farmacologíaRESUMEN
Androgen receptor (AR) signaling inhibitors provide limited survival benefits to patients with prostate cancer (PCa), and worse, few feasible genomic lesions restrict targeted treatment to PCa. Thus, a better understanding of the critical dependencies of PCa may enable more feasible therapeutic approaches to the dilemma. We performed a kinome-scale CRISPR/Cas9 screen and identified cyclin-dependent kinase 12 (CDK12) as being conservatively required for PCa cell survival. Suppression of CDK12 by the covalent inhibitor THZ531 led to an obvious anti-PCa effect. Mechanistically, THZ531 downregulated AR signaling and preferentially repressed a distinct class of CDK12 inhibition-sensitive transcripts (CDK12-ISTs), including prostate lineage-specific genes, and contributed to cellular survival processes. Integration of the super-enhancer (SE) landscape and CDK12-ISTs indicated a group of potential PCa oncogenes, further conferring the sensitivity of PCa cells to CDK12 inhibition. Importantly, THZ531 strikingly synergized with multiple AR antagonists. The synergistic effect may be driven by attenuated H3K27ac signaling on AR targets and an intensive SE-associated apoptosis pathway. In conclusion, we highlight the validity of CDK12 as a druggable target in PCa. The synergy of THZ531 and AR antagonists suggests a potential combination therapy for PCa.
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Sistemas CRISPR-Cas/genética , Quinasas Ciclina-Dependientes/metabolismo , Neoplasias de la Próstata/enzimología , Antagonistas de Andrógenos/farmacología , Anilidas/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Sinergismo Farmacológico , Epigénesis Genética/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Pirimidinas/farmacología , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Undifferentiation is a key feature of nasopharyngeal carcinoma (NPC), which presents as a unique opportunity for intervention by differentiation therapy. In this study, we found that SOX1 inhibited proliferation, promoted differentiation, and induced senescence of NPC cells, which depended on its transcriptional function. RNA-Seq-profiling analysis showed that multiple undifferentiated markers of keratin family, including KRT5, KRT13, and KRT19, were reduced in SOX1 overexpressed NPC cells. Interestingly, gene ontology (GO) analysis revealed genes in SOX1 overexpressed cells were enriched in extracellular functions. The data of LC/MS untargeted metabolomics showed that the content of retinoids in SOX1 overexpressed cells and culture medium was both higher than that in the control group. Subsequently, we screened mRNA level of genes in retinoic acid (RA) signaling or metabolic pathway and found that the expression of UDP-glucuronosyltransferases was significantly decreased. Furtherly, UGT2B7 could rescue the differentiation induced by SOX1 overexpression. Inhibition of UGTs by demethylzeylasteral (T-96) could mimic SOX1 to promote the differentiation of NPC cells. Thus, we described a mechanism by which SOX1 regulated the differentiation of NPC cells by activating retinoid metabolic pathway, providing a potential target for differentiation therapy of NPC.
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Diferenciación Celular , Redes y Vías Metabólicas , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Retinoides/metabolismo , Factores de Transcripción SOXB1/metabolismo , Línea Celular Tumoral , Glucuronosiltransferasa/metabolismo , Células HEK293 , Proteínas HMGB/metabolismo , Humanos , Queratinas/genética , Queratinas/metabolismo , Transcripción GenéticaRESUMEN
Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor-normal samples, we have identified a hotspot mutation (c.419T>C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-κB more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-κB, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-κB from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS.
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Proteínas Adaptadoras Transductoras de Señales/genética , Inflamación/genética , Linfohistiocitosis Hemofagocítica/genética , Linfoma Extranodal de Células NK-T/genética , Proteínas Adaptadoras Transductoras de Señales/química , Adulto , Calgranulina A/química , Calgranulina A/genética , Calgranulina B/química , Calgranulina B/genética , Dexametasona/administración & dosificación , Femenino , Técnicas de Sustitución del Gen , Xenoinjertos , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Interferón gamma/genética , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/fisiopatología , Linfoma Extranodal de Células NK-T/complicaciones , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/fisiopatología , Masculino , Persona de Mediana Edad , Mutación , FN-kappa B/genética , Multimerización de Proteína/genética , Transducción de Señal , Talidomida/administración & dosificación , Factor de Transcripción ReIA/genética , Factor de Necrosis Tumoral alfa/genética , Secuenciación del ExomaRESUMEN
Mechanism for the malignant phenotype of nasopharyngeal carcinoma (NPC) remains poorly understood. Epstein-Barr virus (EBV) consistently appears in nearly all malignant NPC patient samples, suggesting the strong etiological link between the malignant phenotype and EBV infection. Here we found that the EBV-encoded latent membrane protein (LMP1) enhanced cell growth, motility, invasion and xenograft tumor growth of NPC. RNA-seq profiling analysis of LMP1-positive NPC patient tissues indicated that widespread gene repression contributed to malignant phenotype of NPC. The transcription factor binding site (TFBS) enrichment analysis indicated a subset of transcription factors including ATOH8, a novel transcript factor which belongs to the basic helix-loop-helix (bHLH) gene family inversely enriched in promoters of up-regulated genes and down-regulated genes. Importantly, the expression of ATOH8 was suppressed in both immortalized normal nasopharyngeal epithelial cells (NPEC) and NPC cells with LMP1 overexpression. The Real-Time PCR and Western Blot assays indicated that ATOH8 decreased expression in NPC cell lines and patient samples. Moreover, by gain- or loss-of-function assays, we demonstrated that ATOH8 inhibition promoted malignant phenotype, whereas ATOH8 restoration reversed malignant phenotype of NPC. Finally, we demonstrated that LMP1 inhibited ATOH8 expression by epigenetically impairing the occupancy of activating H3K4me3 and enhancing the occupancy of repressive H3K27me3 on ATOH8 promoter. Collectively, our study uncovered the occurrence of malignant phenotype of NPC induced by EBV infection and characterized a novel bHLH transcription factor ATOH8 as a new downstream target of LMP1.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Carcinoma/patología , Infecciones por Virus de Epstein-Barr/complicaciones , Regulación Neoplásica de la Expresión Génica/fisiología , Neoplasias Nasofaríngeas/patología , Proteínas de la Matriz Viral/metabolismo , Animales , Carcinoma/metabolismo , Carcinoma/virología , Regulación hacia Abajo , Xenoinjertos , Humanos , Ratones , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/virología , FenotipoRESUMEN
The relationship between alcohol drinking and the prognosis of nasopharyngeal carcinoma (NPC) is unknown. To investigate the prognostic value of alcohol drinking on NPC, this retrospective study was conducted on 1923 male NPC patients. Patients were classified as current, former and non-drinkers according to their drinking status. Furthermore, they were categorized as heavy drinkers and mild/none drinkers based on the intensity and duration of alcohol drinking. Survival outcomes were compared using Kaplan-Meier analysis and Cox proportional hazards model. We found that current drinkers had significantly lower overall survival (OS) rate (5-year OS: 70.2% vs. 76.4%, P < 0.001) and locoregional recurrence-free survival (LRFS) rate (5-year LRFS: 69.3% vs. 77.5%, P < 0.001) compared with non-drinkers. Drinking ≥14 drinks/week, and drinking ≥20 years were both independent unfavorable prognostic factors for OS (hazard ratio [HR] = 1.38, 95% confidence interval [CI] 1.05-1.81, P = 0.022; HR = 1.38, 95% CI 1.09-1.75, P = 0.007). Stratified analyses further revealed that the negative impacts of alcohol were manifested mainly among older patients and among smokers. In conclusion, alcohol drinking is a useful predictor of prognosis in male NPC patients; drinkers, especially heavy drinkers have poorer prognosis.