RESUMEN
Inhibitor of growth 5 (ING5) has been reported to be involved in the malignant progression of cancers. Ursolic acid (UA) has shown remarkable antitumor effects. However, its antitumor mechanisms regarding of ING5 in hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UA significantly suppressed the proliferation, anti-apoptosis, migration and invasion of HCC cells. In addition, ING5 expression in HCC cells treated with UA was obviously downregulated in a concentration- and time-dependent manner. Additionally, the pro-oncogenic role of ING5 was confirmed in HCC cells. Further investigation revealed that UA exerted antitumor effects on HCC by inhibiting ING5-mediated activation of PI3K/Akt pathway. Notably, UA could also reverse sorafenib resistance of HCC cells by suppressing the ING5-ACC1/ACLY-lipid droplets (LDs) axis. UA abrogated ING5 transcription and downregulated its expression by reducing SRF and YY1 expression and the SRF-YY1 complex formation. Alb/JCPyV T antigen mice were used for in vivo experiments since T antigen upregulated ING5 expression by inhibiting the ubiquitin-mediated degradation and promoting the T antigen-SRF-YY1-ING5 complex-associated transcription. UA suppressed JCPyV T antigen-induced spontaneous HCC through inhibiting ING5-mediated PI3K/Akt signaling pathway. These findings suggest that UA has the dual antitumoral functions of inhibiting hepatocellular carcinogenesis and reversing sorafenib resistance of HCC cells through targeting ING5, which could serve as a potential therapeutic strategy for HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Sorafenib , Triterpenos , Ácido Ursólico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Triterpenos/farmacología , Triterpenos/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéutico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Humanos , Ratones , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Apoptosis/efectos de los fármacos , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Introduction: Cell death regulation holds a unique value in the field of cancer therapy. Recently, disulfidptosis has garnered substantial scientific attention. Previous studies have reported that sonodynamic therapy (SDT) based on reactive oxygen species (ROS) can regulate cancer cell death, achieving an limited anti-cancer effect. However, the integration of SDT with disulfidptosis as an anti-cancer strategy has not been extensively developed. In this study, we constructed an artificial membrane disulfidptosis sonosensitizer, specifically, a nanoliposome (SC@lip) coated with a combination of the chemotherapy medicine Sorafenib (Sora) and sonosensitizer Chlorin e6 (Ce6), to realize a one-stop enhanced SDT effect that induces disulfidptosis-like cancer cell death. Methods: Sorafenib and Ce6 were co-encapsulated into PEG-modified liposomes, and SC@Lip was constructed using a simple rotary evaporation phacoemulsification method. The cell phagocytosis, ROS generation ability, glutathione (GSH) depletion ability, lipid peroxidation (LPO), and disulfidptosis-like death mediated by SC@Lip under ultrasound (US) irradiation were evaluated. Based on a 4T1 subcutaneous tumor model, both the in vivo biological safety assessment and the efficacy of SDT were assessed. Results: SC@Lip exhibits high efficiency in cellular phagocytosis. After being endocytosed by 4T1 cells, abundant ROS were produced under SDT activation, and the cell survival rates were below 5%. When applied to a 4T1 subcutaneous tumor model, the enhanced SDT mediated by SC@Lip inhibited tumor growth and prolonged the survival time of mice. In vitro and in vivo experiments show that SC@Lip can enhance the SDT effect and trigger disulfidptosis-like cancer cell death, thus achieving anti-tumor efficacy both in vitro and in vivo. Conclusion: SC@Lip is a multifunctional nanoplatform with an artificial membrane, which can integrate the functions of sonosensitization and GSH depletion into a biocompatible nanoplatform, and can be used to enhance the SDT effect and promote disulfidptosis-like cancer cell death.
Asunto(s)
Clorofilidas , Peroxidación de Lípido , Liposomas , Porfirinas , Especies Reactivas de Oxígeno , Sorafenib , Terapia por Ultrasonido , Animales , Liposomas/química , Peroxidación de Lípido/efectos de los fármacos , Sorafenib/farmacología , Sorafenib/química , Terapia por Ultrasonido/métodos , Ratones , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Porfirinas/química , Porfirinas/farmacología , Porfirinas/administración & dosificación , Femenino , Ratones Endogámicos BALB C , Nanopartículas/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Glutatión/metabolismo , Muerte Celular/efectos de los fármacosRESUMEN
Carcinoma of the colon and rectum, also known as colorectal cancer, ranks as the third most frequently diagnosed malignancy globally. Sorafenib exhibits broad-spectrum antitumor activity against Raf, VEGF, and PDGF pathways in hepatocellular, thyroid, and renal cancers, but faces resistance in colorectal malignancies. 6-Shogaol, a prominent natural compound found in Zingiberaceae, exhibits antioxidant, anti-inflammatory, anticancer, and antiemetic properties. We investigated the influence of 6-shogaol on sorafenib's cytotoxic profile against colorectal cancer cell lines (HT-29, HCT-116, CaCo-2, and LS174T) through its effects on cellular accumulation and metabolism. Cytotoxicity was assessed using the sulpharodamine B assay, caspase-3 and c-PARP cleavage, cell cycle distribution analysis, and P-gp efflux activity. 6-Shogoal showed considerable cytotoxicity with decreased IC50 in colorectal cancer cell lines. Combining sorafenib and 6-shogaol increased c-PARP and pro-caspase-3 concentrations in HCT-116 cells compared to sorafenib alone. In combination, pro-caspase-3 concentrations were decreased in CaCo-2 cells compared to alone. Sorafenib combinations with 6-shogaol showed a significant drop in cell cycle distribution from 16.96±1.10â¯% to 9.16±1.85â¯%, respectively. At 100⯵M, sorafenib and 6-shogaol showed potent and significant activity with intra-cellular rhodamine concentration on P-gp efflux activity in CRC cell lines. In conclusion, 6-shogaol substantially improved the cytotoxic profile of sorafenib by affecting its cellular uptake and metabolism. Future research should focus on dosage optimization and formulation and evaluate the efficacy and safety of the combination in animal models with colorectal cancer.
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Catecoles , Neoplasias Colorrectales , Sorafenib , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Sorafenib/farmacología , Catecoles/farmacología , Antineoplásicos/farmacología , Sinergismo Farmacológico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Células CACO-2 , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. α-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such α-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects.
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Doxazosina , Células Endoteliales , Hipertensión , Receptores de Factores de Crecimiento Endotelial Vascular , Animales , Perros , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Doxazosina/farmacología , Doxazosina/uso terapéutico , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Proteómica/métodos , Presión Sanguínea/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Lisinopril/farmacología , Lisinopril/uso terapéutico , Masculino , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéuticoRESUMEN
AIM: This study aimed to investigate the role of discoidin domain receptor tyrosine kinase 1 (DDR1) in liver hepatocellular carcinoma (LIHC) and to evaluate its prognostic value on patient response to combination therapy. METHODS: In the current retrospective study, we examined the protein expression of DDR1 in various cancers by standard immunohistochemical (IHC) methods and evaluated its clinical significance in LIHC personalized treatment. Multiple online databases, including The Cancer Genome Atlas (TCGA), TIMER, GEO, ROC Plotter, and Genomics of Drug Sensitivity in Cancer (GDSC), were used. RESULTS: DDR1 protein expression was higher in LIHC than in other nine examined cancer types. Additionally, DDR1 exhibited higher expression levels in adjacent normal tissues compared to HBs-positive LIHC tissues. Analysis at single-cell resolution revealed that DDR1 was expressed primarily in epithelial cells but not in stromal and immune cells, and DDR1 expression was lower in HBs-positive LIHC cells in comparison with normal hepatocytes. Correlation of DDR1 upregulation and sorafenib resistance was observed in the patient cohort. Moreover, DDR1 expression positively correlated with the expression of inflammatory response-related genes, ECM-related genes, and collagen formation-related genes, but negatively correlated with the infiltration of CD8+ T cells, NK cells, and dendritic cells in LIHC. CONCLUSIONS: Our findings suggest that DDR1 expression might be induced by collagen production-related cellular events involved in liver injury and repair, and that DDR1 overexpression might contribute to the resistance to LIHC targeted therapy and immunotherapy, highlighting DDR1 as a potential prognostic biomarker and therapeutic target.
This study aimed to investigate the role of discoidin domain receptor tyrosine kinase 1 (DDR1) in liver hepatocellular carcinoma (LIHC) and to evaluate its prognostic value on patient response to combination therapy. In the current retrospective study, we examined the protein expression of DDR1 in various cancers by standard immunohistochemical (IHC) methods and evaluated its clinical significance in LIHC personalized treatment. Multiple online databases, including The Cancer Genome Atlas (TCGA), TIMER, GEO, ROC Plotter, and Genomics of Drug Sensitivity in Cancer (GDSC), were used. DDR1 protein expression was higher in LIHC than in other nine examined cancer types. Additionally, DDR1 exhibited higher expression levels in adjacent normal tissues compared to HBs-positive LIHC tissues. Analysis at single-cell resolution revealed that DDR1 was expressed primarily in epithelial cells but not stromal cells and immune cells, and DDR1 expression was lower in HBs-positive LIHC cells in comparison with normal hepatocytes. Correlation of DDR1 upregulation and sorafenib resistance was observed in patient cohort. Moreover, DDR1 expression positively correlated with the expression of inflammatory response-related genes, ECM-related genes, and collagen formation-related genes but negatively correlated with the infiltration of CD8 + T cells, NK cells, and dendritic cells in LIHC. Our findings suggest that DDR1 expression might be induced by collagen production-related cellular events involved in liver injury and repair and that DDR1 overexpression might contribute to the resistance to LIHC targeted therapy and immunotherapy, highlighting DDR1 as a potential prognostic biomarker and therapeutic target.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Hepatocelular , Receptor con Dominio Discoidina 1 , Neoplasias Hepáticas , Sorafenib , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Receptor con Dominio Discoidina 1/metabolismo , Receptor con Dominio Discoidina 1/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Estudios Retrospectivos , Sorafenib/uso terapéutico , Sorafenib/farmacología , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Resistencia a Antineoplásicos/genéticaRESUMEN
The poor prognosis of hepatocellular carcinoma (HCC) is still an urgent challenge to be solved worldwide. Hence, assembling drugs and targeted short peptides together to construct a novel medicine delivery strategy is crucial for targeted and synergy therapy of HCC. Herein, a high-efficiency nanomedicine delivery strategy has been constructed by combining graphdiyne oxide (GDYO) as a drug-loaded platform, specific peptide (SP94-PEG) as a spear to target HCC cells, sorafenib, doxorubicin-Fe2+ (DOX-Fe2+), and siRNA (SLC7A11-i) as weapons to exert a three-path synergistic attack against HCC cells. In this work, SP94-PEG and GDYO form nanosheets with HCC-targeting properties, the chemotherapeutic drug DOX linked to ferrous ions increases the free iron pool in HCC cells and synergizes with sorafenib to induce cell ferroptosis. As a key gene of ferroptosis, interference with the expression of SLC7A11 makes the ferroptosis effect in HCC cells easier, stronger, and more durable. Through gene interference, drug synergy, and short peptide targeting, the toxic side effects of chemotherapy drugs are reduced. The multifunctional nanomedicine GDYO@SP94/DOX-Fe2+/sorafenib/SLC7A11-i (MNMG) possesses the advantages of strong targeting, good stability, the ability to continuously induce tumor cell ferroptosis and has potential clinical application value, which is different from traditional drugs.
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Carcinoma Hepatocelular , Doxorrubicina , Ferroptosis , Neoplasias Hepáticas , Nanomedicina , Péptidos , Sorafenib , Ferroptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Doxorrubicina/farmacología , Doxorrubicina/química , Nanomedicina/métodos , Sorafenib/farmacología , Sorafenib/química , Línea Celular Tumoral , Animales , Péptidos/química , Péptidos/farmacología , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Sinergismo Farmacológico , Sistema de Transporte de Aminoácidos y+/metabolismo , Ratones Desnudos , ARN Interferente Pequeño , Ratones Endogámicos BALB C , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, with a high mortality rate due to the limited therapeutic options. Systemic drug treatments improve the patient's life expectancy by only a few months. Furthermore, the development of novel small molecule chemotherapeutics is time-consuming and costly. Drug repurposing has been a successful strategy for identifying and utilizing new therapeutic options for diseases with limited treatment options. This study aims to identify candidate drug molecules for HCC treatment through repurposing existing compounds, leveraging the machine learning tool MDeePred. The Open Targets Platform, UniProt, ChEMBL, and Expasy databases were used to create a dataset for drug target interaction (DTI) predictions by MDeePred. Enrichment analyses of DTIs were conducted, leading to the selection of 6 out of 380 DTIs identified by MDeePred for further analyses. The physicochemical properties, lipophilicity, water solubility, drug-likeness, and medicinal chemistry properties of the candidate compounds and approved drugs for advanced stage HCC (lenvatinib, regorafenib, and sorafenib) were analyzed in detail. Drug candidates exhibited drug-like properties and demonstrated significant target docking properties. Our findings indicated the binding efficacy of the selected drug compounds to their designated targets associated with HCC. In conclusion, we identified small molecules that can be further exploited experimentally in HCC therapeutics. Our study also demonstrated the use of the MDeePred deep learning tool in in silico drug repurposing efforts for cancer therapeutics.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Reposicionamiento de Medicamentos , Neoplasias Hepáticas , Simulación del Acoplamiento Molecular , Reposicionamiento de Medicamentos/métodos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéutico , Sorafenib/química , Aprendizaje Automático , Compuestos de Fenilurea/química , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/farmacología , PiridinasRESUMEN
Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor prognosis. The available drugs for advanced HCC are limited and substantial therapeutic advances including new drugs and new combination therapies are still in urgent need. In this study, we found that the major metabolite of Lactobacillus reuteri (L. reuteri), reuterin showed great anti-HCC potential and could help in sorafenib treatment. Reuterin treatment impaired mitophagy and caused the aberrant clustering of mitochondrial nucleoids to block mitochondrial DNA (mtDNA) replication and mitochondrial fission, which could promote mtDNA leakage and subsequent STING activation in HCC cells. STING could activate pyroptosis and necroptosis, while reuterin treatment also induced caspase 8 expression to inhibit necroptosis through cleaving RIPK3 in HCC cells. Thus, pyroptosis was the main death form in reuterin-treated HCC cells and STING suppression remarkably rescued the growth inhibitory effect of reuterin and concurrently knockdown caspase 8 synergized to restrain the induction of pyroptosis. In conclusion, our study explains the detailed molecular mechanisms of the antitumor effect of reuterin and reveals its potential to perform as a combinational drug for HCC treatment.
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Carcinoma Hepatocelular , Caspasa 8 , ADN Mitocondrial , Neoplasias Hepáticas , Proteínas de la Membrana , Piroptosis , Humanos , Piroptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Caspasa 8/metabolismo , Caspasa 8/genética , ADN Mitocondrial/genética , Línea Celular Tumoral , Animales , Ratones , Sorafenib/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Sorafenib is widely used in treating advanced hepatocellular carcinoma (HCC). However, its effectiveness in prolonging patient survival is limited by the development of drug resistance. To systematically investigate the resistance mechanisms of Sorafenib, an integrative analysis combining posttranslational modification (PTM) omics and CRISPR/Cas9 knockout library screening was conducted. This analysis identified ubiquitination at lysine 21 (K21) on chaperonin-containing TCP1 subunit 3 (CCT3) as being associated with Sorafenib resistance. Transcriptomic data from HCC patients treated with Sorafenib revealed that CCT3 expression was lower in responders compared to non-responders. Experimentally, inhibiting the expression of CCT3 sensitized HCC cells to Sorafenib and enhanced Sorafenib-induced ferroptosis. Additionally, CCT3 was found to interact with ACTN4, hindering the recycling of transferrin receptor protein 1 (TFRC) to the cell membrane, thus obstructing iron endocytosis. Mechanistically, the inhibition of ferroptosis by CCT3 depends on the deubiquitination of K6-linked non-degradative ubiquitination at its K21, which occurs upon Sorafenib treatment. Moreover, CCT3 knockdown enhanced the anti-tumor effects of Sorafenib in nude mice. In summary, we have identified a novel function of the chaperone protein. Targeting the CCT3/ACTN4/TFRC axis offers a promising strategy to enhance ferroptosis and overcome Sorafenib resistance in HCC.
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Carcinoma Hepatocelular , Ferroptosis , Hierro , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Humanos , Ferroptosis/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Ratones , Animales , Hierro/metabolismo , Endocitosis , Ratones Desnudos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Chaperonina con TCP-1/metabolismo , Chaperonina con TCP-1/genética , Línea Celular Tumoral , Receptores de Transferrina/metabolismo , MasculinoRESUMEN
BACKGROUND: This study investigates the molecular mechanisms of CC@AC&SF@PP NPs loaded with AC099850.3 siRNA and sorafenib (SF) for improving hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). METHODS: A dataset of 44 HBV-HCC patients and their survival information was selected from the TCGA database. Immune genes related to survival status were identified using the ImmPort database and WGCNA analysis. A prognostic risk model was constructed and analyzed using Lasso regression. Differential analysis was performed to screen key genes, and their significance and predictive accuracy for HBV-HCC were validated using Kaplan-Meier survival curves, ROC analysis, CIBERSORT analysis, and correlation analysis. The correlation between AC099850.3 and the gene expression matrix was calculated, followed by GO and KEGG enrichment analysis using AC099850.3 and its co-expressed genes. HepG2.2.15 cells were selected for in vitro validation, and lentivirus interference, cell cycle determination, CCK-8 experiments, colony formation assays, Transwell experiments, scratch experiments, and flow cytometry were performed to investigate the effects of key genes on HepG2.2.15 cells. A subcutaneous transplanted tumor model in mice was constructed to verify the inhibitory effect of key genes on HBV-HCC tumors. Subsequently, pH-triggered drug release NPs (CC@AC&SF@PP) were prepared, and their therapeutic effects on HBV-HCC in situ tumor mice were studied. RESULTS: A prognostic risk model (AC012313.9, MIR210HG, AC099850.3, AL645933.2, C6orf223, GDF10) was constructed through bioinformatics analysis, showing good sensitivity and specificity in diagnostic prediction. AC099850.3 was identified as a key gene, and enrichment analysis revealed its impact on cell cycle pathways. In vitro cell experiments demonstrated that AC099850.3 promotes HepG2.2.15 cell proliferation and invasion by regulating immune checkpoint CD276 expression and cell cycle progression. In vivo, subcutaneously transplanted tumor experiments showed that AC099850.3 promotes the growth of HBV-HCC tumors in nude mice. Furthermore, pH-triggered drug release NPs (CC@AC&SF@PP) loaded with AC099850.3 siRNA and SF were successfully prepared and delivered to the in situ HBV-HCC, enhancing the effectiveness of combined therapy for HBV-HCC. CONCLUSIONS: AC099850.3 accelerates the cell cycle progression and promotes the occurrence and development of HBV-HCC by upregulating immune checkpoint CD276 expression. CC@AC&SF@PP NPs loaded with AC099850.3 siRNA and SF improve the effectiveness of combined therapy for HBV-HCC.
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Antígenos B7 , Carcinoma Hepatocelular , Proliferación Celular , Virus de la Hepatitis B , Neoplasias Hepáticas , Invasividad Neoplásica , Sorafenib , Humanos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/virología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/virología , Proliferación Celular/efectos de los fármacos , Animales , Antígenos B7/metabolismo , Antígenos B7/genética , Células Hep G2 , Virus de la Hepatitis B/efectos de los fármacos , Ratones Desnudos , Ratones , Quitosano/química , Quitosano/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Masculino , Hepatitis B/tratamiento farmacológico , Hepatitis B/virología , Ratones Endogámicos BALB CRESUMEN
In advanced hepatocellular carcinoma (HCC), RNA helicase DDX5 regulates the Wnt/ß-catenin-ferroptosis axis, influencing the efficacy of the multi-tyrosine kinase inhibitor (mTKI) sorafenib. DDX5 inhibits Wnt/ß-catenin signaling, preventing sorafenib-induced ferroptosis escape. Sorafenib/mTKIs reduce DDX5 expression, correlating with poor patient survival post-sorafenib treatment. Notably, DDX5-knockout in HCC cells activates Wnt/ß-catenin signaling persistently. Herein, we investigate the mechanistic impact of Wnt/ß-catenin activation resulting from DDX5 downregulation in the progression and treatment of HCC. RNAseq analyses identified shared genes repressed by DDX5 and upregulated by sorafenib, including Wnt signaling genes, NF-κB-inducing kinase (NIK) essential for non-canonical NF-κB (p52/RelB) activation, and cytoprotective transcription factor NRF2. We demonstrate, Wnt/ß-catenin activation induced NIK transcription, leading to non-canonical NF-κB activation, which subsequently mediated NRF2 transcription. Additionally, DDX5 deficiency extended NRF2 protein half-life by inactivating KEAP1 through p62/SQSTM1 stabilization. In a preclinical HCC mouse model, NRF2 knockdown or DDX5 overexpression restricted tumor growth upon sorafenib treatment, via induction of ferroptosis. Importantly, DDX5-knockout HCC cells exhibited elevated expression of Wnt signaling genes, NIK, p52/RelB, and NRF2-regulated genes, regardless of sorafenib treatment. Transcriptomic analyses of HCCs from TCGA and the Stelic Animal Model (STAM) of non-alcoholic steatohepatitis revealed elevated expression of these interconnected pathways in the context of DDX5 downregulation. In conclusion, DDX5 deficiency triggers Wnt/ß-catenin signaling, promoting p52/RelB and NRF2 activation, thereby enabling ferroptosis evasion upon sorafenib treatment. Similarly, independent of sorafenib, DDX5 deficiency in liver tumors enhances activation and gene expression of these interconnected pathways, underscoring the clinical relevance of DDX5 deficiency in HCC progression and therapeutic response.
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Carcinoma Hepatocelular , ARN Helicasas DEAD-box , Progresión de la Enfermedad , Neoplasias Hepáticas , Factor 2 Relacionado con NF-E2 , FN-kappa B , Sorafenib , Sorafenib/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Animales , Humanos , Ratones , FN-kappa B/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Línea Celular Tumoral , Vía de Señalización Wnt/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Ferroptosis/genéticaRESUMEN
The five-year survival rate for patients with hepatocellular carcinoma (HCC) is only 20â¯%, highlighting the urgent need to identify new therapeutic targets and develop potential therapeutic options to improve patient prognosis. One promising approach is inhibiting autophagy as a strategy for HCC treatment. In this study, we established a virtual docking conformation of the autophagy promoter ULK1 binding XST-14 derivatives. Based on this conformation, we designed and synthesized four series of derivatives. By evaluating their affinity and anti-HCC effects, we confirmed that these compounds exert anti-HCC activity by inhibiting ULK1. The structure-activity relationship was summarized, with derivative A4 showing 10 times higher activity than XST-14 and superior efficacy to sorafenib against HCC. A4 has excellent effect on reducing tumor growth and enhancing sorafenib activity in HepG2 and HCCLM3 cells. Moreover, we verified the therapeutic effect of A4 in sorafenib-resistant HCC cells both in vivo and in vitro. These results suggest that inhibiting ULK1 to regulate autophagy may become a new treatment method for HCC and that A4 will be used as a lead drug for HCC in further research. Overall, A4 shows good drug safety and efficacy, offering hope for prolonging the survival of HCC patients.
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Antineoplásicos , Carcinoma Hepatocelular , Diseño de Fármacos , Indoles , Neoplasias Hepáticas , Inhibidores de Proteínas Quinasas , Sorafenib , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Autofagia/efectos de los fármacos , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Indoles/farmacología , Indoles/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Sorafenib/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hepatocellular carcinoma (HCC) has risen as the villain of cancer-related death globally, with a usual cruel forecasting. Sorafenib was officially approved by the FDA as first-line treatment for advanced HCC. Despite the brilliant promise revealed in research, actual clinical results are limited due to the widespread appearance of drug resistance. The tumor microenvironment (TME) has been correlated to pharmacological resistance, implying that existing cellular level strategies may be insufficient to improve therapy success. The role of autophagy in cancer is a two-edged sword. On one hand, autophagy permits malignant cells to overcome stress, such as hypoxic TME and therapy-induced starvation. Autophagy, on the other hand, plays an important role in damage suppression, which can reduce carcinogenesis. As a result, controlling autophagy is certainly a viable technique in cancer therapy. The goal of this study was to investigate at the impact of autophagy manipulation with sorafenib therapy by analyzing autophagy induction and inhibition to sorafenib monotherapy in rats with HCC. Western blot, ELISA, immunohistochemistry, flow cytometry, and quantitative-PCR were used to investigate autophagy, apoptosis, and the cell cycle. Routine biochemical and pathological testing was performed. Ultracellular features and autophagic entities were observed using a transmission electron microscope (TEM). Both regimens demonstrated significant reductions in chemotherapeutic resistance and hepatoprotective effects. According to the findings, both autophagic inhibitors and inducers are attractive candidates for combating sorafenib-induced resistance in HCC.
Asunto(s)
Autofagia , Carcinoma Hepatocelular , Resistencia a Antineoplásicos , Neoplasias Hepáticas , Sorafenib , Sorafenib/farmacología , Sorafenib/uso terapéutico , Animales , Autofagia/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Ratas , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Masculino , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Considering the profound impact of structure on heterojunction catalysts, the rational design of emerging catalysts with optimized energy band structures is required for antitumor efficiency. Herein, we select titanium nitride (TiN) and Pt to develop a multifunctional Schottky heterojunction named Pt/H-TiN&SRF (PHTS) nanoparticles (NPs) with a narrowed bandgap to accomplish "four birds with one stone" involving enzyo/sono/photo three modals and additional ferroptosis. The in situ-grown Pt NPs acted as electron traps that can cause the energy band to bend upward and form a Schottky barrier, thereby facilitating the separation of electron/hole pairs in exogenous stimulation catalytic therapy. In addition, endogenous catalytic reactions based on peroxidase (POD)- and catalase (CAT)-mimicking activities can also be amplified, triggering intense oxidative stress, in which CAT-like activity decomposes endogenous H2O2 into O2 alleviating hypoxia and provides reactants for sonodynamic therapy. Moreover, PHTS NPs can elicit mild photothermal therapy with boosted photothermal properties as well as ferroptosis with loaded ferroptosis inducer sorafenib for effective tumor ablation and apoptosis-ferroptosis synergistic tumor inhibitory effect. In summary, this paper proposes an attractive design for antitumor strategies and highlights findings for heterojunction catalytic therapy with potential in tumor theranostics.
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Antineoplásicos , Titanio , Animales , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Humanos , Titanio/química , Titanio/farmacología , Ferroptosis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Platino (Metal)/química , Platino (Metal)/farmacología , Sorafenib/farmacología , Sorafenib/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Terapia Fototérmica , Nanopartículas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Approximately 25-30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML. METHODS: We performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked immunosorbent assays to determine potential drivers of sorafenib resistance. FLT3 signaling was inhibited by sorafenib or quizartinib, and SPHK1 was inhibited by using an antagonist or via knockdown. Cell growth and apoptosis were assessed in FLT3-mutated and wild-type AML cell lines via Cell counting kit-8, PI staining, and Annexin-V/7AAD assays. Western blotting and immunofluorescence assays were employed to explore the underlying molecular mechanisms through rescue experiments using SPHK1 overexpression and exogenous S1P, as well as inhibitors of S1P2, ß-catenin, PP2A, and GSK3ß. Xenograft murine model, patient samples, and publicly available data were analyzed to corroborate our in vitro results. RESULTS: We demonstrate that long-term sorafenib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates ß-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit ß-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3ß (GSK3ß) pathway. CONCLUSIONS: These findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.
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Glucógeno Sintasa Quinasa 3 beta , Leucemia Mieloide Aguda , Fosfotransferasas (Aceptor de Grupo Alcohol) , Proteína Fosfatasa 2 , beta Catenina , Tirosina Quinasa 3 Similar a fms , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , beta Catenina/metabolismo , beta Catenina/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Animales , Ratones , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/antagonistas & inhibidores , Línea Celular Tumoral , Sorafenib/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genéticaRESUMEN
Translation is one of the main gene expression steps targeted by cellular stress, commonly referred to as translational stress, which includes treatment with anticancer drugs. While translational stress blocks the translation initiation of bulk mRNAs, it nonetheless activates the translation of specific mRNAs known as short upstream open reading frames (uORFs)-mRNAs. Among these, the ATF4 mRNA encodes a transcription factor that reprograms gene expression in cells responding to various stresses. Although the stress-induced translation of the ATF4 mRNA relies on the presence of uORFs (upstream to the main ATF4 ORF), the mechanisms mediating this effect, particularly during chemoresistance, remain elusive. Here, we report that ALKBH5 (AlkB Homolog 5) and FTO (FTO: Fat mass and obesity-associated protein), the two RNA demethylating enzymes, promote the translation of ATF4 mRNA in a transformed liver cell line (Hep3B) treated with the chemotherapeutic drug sorafenib. Using the in vitro luciferase reporter translational assay, we found that depletion of both enzymes reduced the translation of the reporter ATF4 mRNA upon drug treatment. Consistently, depletion of either protein abrogates the loading of the ATF3 mRNA into translating ribosomes as assessed by polyribosome assays coupled to RT-qPCR. Collectively, these results indicate that the ALKBH5 and FTO-mediated translation of the ATF4 mRNA is regulated at its initiation step. Using in vitro methylation assays, we found that ALKBH5 is required for the inhibition of the methylation of a reporter ATF4 mRNA at a conserved adenosine (A235) site located at its uORF2, suggesting that ALKBH5-mediated translation of ATF4 mRNA involves demethylation of its A235. Preventing methylation of A235 by introducing an A/G mutation into an ATF4 mRNA reporter renders its translation insensitive to ALKBH5 depletion, supporting the role of ALKBH5 demethylation activity in translation. Finally, targeting either ALKBH5 or FTO sensitizes Hep3B to sorafenib-induced cell death, contributing to their resistance. In summary, our data show that ALKBH5 and FTO are novel factors that promote resistance to sorafenib treatment, in part by mediating the translation of ATF4 mRNA.
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Factor de Transcripción Activador 4 , Desmetilasa de ARN, Homólogo 5 de AlkB , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Mensajero , Sorafenib , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Sorafenib/farmacología , Humanos , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Línea Celular Tumoral , Biosíntesis de Proteínas/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacologíaRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant tumor known for its hypoxic environment, which contributes to resistance against the anticancer drug Sorafenib (SF). Addressing SF resistance in HCC requires innovative strategies to improve tumor oxygenation and effectively deliver therapeutics. RESULTS: In our study, we explored the role of KPNA4 in mediating hypoxia-induced SF resistance in HCC. We developed hemoglobin nanoclusters (Hb-NCs) capable of carrying oxygen, loaded with indocyanine green (ICG) and SF, named HPRG@SF. In vitro, HPRG@SF targeted HCC cells, alleviated hypoxia, suppressed KPNA4 expression, and enhanced the cytotoxicity of PDT against hypoxic, SF-resistant HCC cells. In vivo experiments supported these findings, showing that HPRG@SF effectively improved the oxygenation within the tumor microenvironment and countered SF resistance through combined photodynamic therapy (PDT). CONCLUSION: The combination of Hb-NCs with ICG and SF, forming HPRG@SF, presents a potent strategy to overcome drug resistance in hepatocellular carcinoma by improving hypoxia and employing PDT. This approach not only targets the hypoxic conditions that underlie resistance but also provides a synergistic anticancer effect, highlighting its potential for clinical applications in treating resistant HCC.
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Carcinoma Hepatocelular , Hemoglobinas , Verde de Indocianina , Neoplasias Hepáticas , Fotoquimioterapia , Sorafenib , Microambiente Tumoral , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Humanos , Fotoquimioterapia/métodos , Animales , Hemoglobinas/farmacología , Línea Celular Tumoral , Sorafenib/farmacología , Sorafenib/uso terapéutico , Ratones , Verde de Indocianina/química , Verde de Indocianina/farmacología , Verde de Indocianina/uso terapéutico , Ratones Desnudos , Ratones Endogámicos BALB C , Antineoplásicos/farmacología , Antineoplásicos/química , alfa Carioferinas/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Nanopartículas/químicaRESUMEN
BACKGROUND: Ferroptosis is associated with cancer progression and has a promising application for treating hepatocellular carcinoma (HCC). Long non-coding RNA (lncRNA) participates widely in the regulation of ferroptosis, but the key lncRNA regulators implicated in ferroptosis and their molecular mechanisms remain to be identified. METHODS: Bioinformatic analysis was performed in R based on The Cancer Genome Atlas Program (TCGA) public database. The relative expression of genes was detected by real-time quantitative PCR. Cell viability was assessed by the CCK8 assay. The cell cycle and apoptosis were detected by flow cytometry. Migration and invasion of HCC cells were detected by Transwell assay and wound healing assay. Expression of relevant proteins was detected by Western blotting. A dual-luciferase reporter assay was used to detect interactions between PART1 (or SLC7A11) and miR-490-3p. RESULTS: The PART1/miR-490-3p/SLC7A11 axis was identified as a potential regulatory pathway of ferroptosis in HCC. PART1 silencing reduced HCC cell proliferation, migration, and metastasis and promoted apoptosis and erastin-reduced ferroptosis. Further investigation revealed that PART1 acted as a competitive endogenous RNA (ceRNA) for miR-490-3p to enhance SLC7A11 expression. Overexpression of miR-490-3p downregulated the expression of SLC7A11, inhibiting the proliferation, invasion, and metastasis of HCC cells while promoting apoptosis and erastin-induced ferroptosis. Knockdown of PART1 in HCC cells significantly improved the sensitivity of HCC cells to sorafenib. CONCLUSION: Our results revealed that the PART1/miR-490-3p/SLC7A11 axis enhances HCC cell malignancy and suppresses ferroptosis, which provides a new perspective for understanding of the function of long chain non-coding RNAs in HCC. The PART1/miR-490-3p/SLC7A11 axis may be target for improving sorafenib sensitivity in HCC.
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Sistema de Transporte de Aminoácidos y+ , Carcinoma Hepatocelular , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , MicroARNs , ARN Largo no Codificante , Ferroptosis/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Línea Celular Tumoral , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proliferación Celular/genética , Carcinogénesis/genética , Movimiento Celular/genética , Apoptosis/genética , Sorafenib/farmacologíaRESUMEN
Polydopamine nanoparticles (PDA NPs) are proposed as an anti-cancer tool against hepatocellular carcinoma through the combination of near-infrared (NIR)-mediated hyperthermia and loading with a chemotherapeutic drug, sorafenib (SRF). Cell membranes isolated from a liver cancer cell line (HepG2) have been exploited for the coating of the nanoparticles (thus obtaining CM-SRF-PDA NPs), to promote homotypic targeting toward cancer cells. The selective targeting ability and the combined photothermal and chemotherapeutic activity of the CM-SRF-PDA NPs following NIR irradiation have been evaluated on cell cultures in static and dynamic conditions, besides three-dimensional culture models. Eventually, the therapeutic effectiveness of the proposed approach has also been tested ex ovo on HepG2 spheroid-grafted quail embryos. This comprehensive investigation, supported by proteomic analysis, showed the effectiveness of the proposed nanoplatform and strongly suggests further pre-clinical testing in the treatment of liver cancer.
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Antineoplásicos , Indoles , Neoplasias Hepáticas , Nanopartículas , Terapia Fototérmica , Polímeros , Indoles/química , Indoles/farmacología , Polímeros/química , Polímeros/farmacología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Nanopartículas/química , Nanopartículas/uso terapéutico , Células Hep G2 , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Sorafenib/química , Sorafenib/farmacología , Sorafenib/uso terapéutico , Supervivencia Celular/efectos de los fármacosRESUMEN
Advanced hepatocellular carcinoma (HCC) patients have poor prognosis. As an endogenous antioxidant enzyme involved in a variety of bioprocesses, sulfiredoxin-1 (SRXN1) plays an irreplaceable role in promoting the development of tumors. However, the role and working mechanism of SRXN1 in HCC remain unclear. In this study, we confirmed that SRXN1 promoted the cell proliferation of HCC at genetic and pharmacological level, respectively. Transcriptome sequencing analysis revealed SRXN1 knockdown had a significant effect on the expression of lysosome biogenesis related genes. Further experiments validated that lysosome biogenesis and autophagic flux were enhanced after SRXN1 inhibition and reduced as SRXN1 overexpression. Mechanism study revealed that ROS accumulation induced TFEB nuclear translocation, followed by increased autophagy. Following this rationale, the combination of SRXN1 inhibitor and sorafenib demonstrated noticeable synergistic antitumor effect through the boost of ROS both in vivo and in vitro. Taken together, SRXN1 could be a potential therapeutic target for HCC therapy.