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1.
J Cell Sci ; 133(9)2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32184263

RESUMO

Under metabolic stress, cellular components can assemble into distinct membraneless organelles for adaptation. One such example is cytidine 5'-triphosphate synthase (CTPS, for which there are CTPS1 and CTPS2 forms in mammals), which forms filamentous structures under glutamine deprivation. We have previously demonstrated that histidine (His)-mediated methylation regulates the formation of CTPS filaments to suppress enzymatic activity and preserve the CTPS protein under glutamine deprivation, which promotes cancer cell growth after stress alleviation. However, it remains unclear where and how these enigmatic structures are assembled. Using CTPS-APEX2-mediated in vivo proximity labeling, we found that synaptosome-associated protein 29 (SNAP29) regulates the spatiotemporal filament assembly of CTPS along the cytokeratin network in a keratin 8 (KRT8)-dependent manner. Knockdown of SNAP29 interfered with assembly and relaxed the filament-induced suppression of CTPS enzymatic activity. Furthermore, APEX2 proximity labeling of keratin 18 (KRT18) revealed a spatiotemporal association of SNAP29 with cytokeratin in response to stress. Super-resolution imaging suggests that during CTPS filament formation, SNAP29 interacts with CTPS along the cytokeratin network. This study links the cytokeratin network to the regulation of metabolism by compartmentalization of metabolic enzymes during nutrient deprivation.


Assuntos
Carbono-Nitrogênio Ligases , Histidina , Animais , Citidina Trifosfato , Histidina/genética , Queratinas
2.
Int J Mol Sci ; 23(14)2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35886860

RESUMO

Exosomal microRNAs (EXO-miRNAs) are promising non-invasive diagnostic biomarkers for cardiovascular disease. Heart failure with preserved ejection fraction (HFpEF) is a poorly understood cardiovascular complication of diabetes mellitus (DM). Little is known about whether EXO-miRNAs can be used as biomarkers for HFpEF in DM. We aimed to investigate the relationship between EXO-miRNAs and HFpEF in STZ-induced diabetic rats. We prepared STZ-induced diabetic rats exhibiting a type 1 DM phenotype with low body weight, hyperglycemia, hyperlipidemia and hypoinsulinemia. Histological sections confirmed atrophy and fibrosis of the heart, with collagen accumulation representing diabetic cardiomyopathy. Significant decreases in end-diastolic volume, stroke volume, stroke work, end-systolic elastance and cardiac output indicated impaired cardiac contractility, as well as mRNA conversion of two isoforms of myosin heavy chain (α-MHC and ß-MHC) and increased atrial natriuretic factor (ANF) mRNA indicating heart failure, were consistent with the features of HFpEF. In diabetic HFpEF rats, we examined a selected panel of 12 circulating miRNAs associated with HF (miR-1-3p, miR-21-5p, miR-29a-5p, miR-30d-5p, miR-34a-5p, miR-126a-5p, miR-143-3p, miR-145-5p, miR-195-5p, miR-206-3p, miR-320-3p and miR-378-3p). Although they were all expressed at significantly lower levels in the heart compared to non-diabetic controls, only six miRNAs (miR-21-5p, miR-30d-5p, miR-126a-5p, miR-206-3p, miR-320-3p and miR-378-3p) were also reduced in exosomal content, while one miRNA (miR-34a-5p) was upregulated. Similarly, although all miRNAs were correlated with reduced cardiac output as a measure of cardiovascular performance, only three miRNAs (miR-30d-5p, miR-126a-5p and miR-378-3p) were correlated in exosomal content. We found that miR-30d-5p and miR-126a-5p remained consistently correlated with significant reductions in exosomal expression, cardiac expression and cardiac output. Our findings support their release from the heart and association with diabetic HFpEF. We propose that these two EXO-miRNAs may be important for the development of diagnostic tools for diabetic HFpEF.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Exossomos , Insuficiência Cardíaca , MicroRNAs , Animais , Biomarcadores , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Exossomos/genética , Insuficiência Cardíaca/genética , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro , Ratos , Volume Sistólico/genética
3.
Mutat Res ; 747(2): 253-8, 2012 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-22721813

RESUMO

Goniothalamin (GTN), a plant bioactive styryl-lactone, is a natural product with potent anti-tumorigenesis effects for several types of cancer. Nonetheless, the anticancer effect of GTN has not been examined in oral cancer. The present study was designed to evaluate its potential anticancer effects in an oral squamous cell carcinoma (OSCC) model and to determine the possible mechanisms with respect to apoptosis, DNA damage, reactive oxygen species (ROS) induction, and mitochondrial membrane potential. Our data demonstrated that cell proliferation was significantly inhibited by GTN in Ca9-22 OSCC cancer cells in concentration- and time-dependent manners (p<0.05). For cell cycle and apoptotic effects of GTN-treated Ca9-22 cancer cells, the sub-G1 population and annexin V-intensity significantly increased in a concentration-dependent manner (p<0.001). For the analysis of DNA double strand breaks, γH2AX intensity significantly increased in GTN-treated Ca9-22 cancer cells in concentration-response relationship (p<0.05). Moreover, GTN significantly induced intracellular ROS levels in Ca9-22 cancer cells in a concentration- and time-dependent manner (p<0.05). For membrane depolarization of mitochondria, the DiOC(2)(3) (3,3'-diethyloxacarbocyanine iodide) intensity of GTN-treated Ca9-22 cancer cells was significantly decreased in concentration- and time-dependent relationships (p<0.001). Taken together, these results suggest that the anticancer effect of GTN against oral cancer cells is valid and GTN-induced growth inhibition and apoptosis influence the downstream cascade including ROS induction, DNA damage, and mitochondria membrane depolarization. Therefore, GTN has potential as a chemotherapeutic agent against oral cancer.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Pironas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
4.
J Mater Chem B ; 8(18): 4122-4131, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32267258

RESUMO

In this study, we demonstrated that zero-valent iron (ZVI), which is widely used to remediate environmental contamination through the production of high-energy reactive oxygen species (ROS), exhibited differential cytotoxicity in cancerous cells and nonmalignant cells. Nanoparticles (NPs) with different shells exhibited distinct potencies against cancerous cells, which depended on their iron-to-oxygen ratios. Silver-coated ZVI NPs (ZVI@Ag) had the highest potency among synthesized ZVI NPs, and they simultaneously exhibited adequate biocompatibility with nonmalignant keratinocytes. The assessment of the intracellular dynamics of iron species revealed that the uptake of ZVI@Ag was similar between cancerous cells and nonmalignant cells during the first 2 h; however, only cancerous cells rapidly converted NPs into iron ions and generated large amounts of intracellular ROS, which was followed by apoptosis and autophagy induction. The aforementioned processes were prevented in the presence of iron ion chelators or by preoxidizing NPs before administration. Neutralization of lysosomal pH effectively reduced ZVI@Ag NP-induced programmed cell death. In the xenograft mouse model, cancer growth was significantly inhibited by a single dose of systematically administered NPs without significant weight loss in animals.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ferro/farmacologia , Lisossomos/efeitos dos fármacos , Nanopartículas/química , Prata/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ferro/química , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Prata/química , Relação Estrutura-Atividade , Propriedades de Superfície , Células Tumorais Cultivadas
5.
Biomater Sci ; 7(4): 1311-1322, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30734774

RESUMO

Addressing nanomedicine resistance is critical for its ultimate clinical success; despite this, advancing the therapeutic designs for cancer therapy are rarely discussed in the literature. In this study, we discovered that ferroptosis is the central mechanism governing the therapeutic efficacy and resistance of treatment with zero-valent iron nanoparticles (ZVI NPs). In ZVI-sensitive oral cancer cells, ZVI NPs-induced ferroptosis was characterized by mitochondrial lipid peroxidation and reduced levels of glutathione peroxidases (GPx) in subcellular organelles. However, resistant cells could attenuate ZVI-induced oxidative stress and GPx reduction. They also showed stronger mitochondrial respiration ability, thus resisting ZVI NPs-induced mitochondrial membrane potential loss. Transcriptome comparison and quantitative polymerase chain reaction (qPCR) analysis revealed that ZVI-resistant cancer cells expressed a gene set related to enhanced NADPH supply, higher detoxification capacity of reactive oxygen species, and decreased sensitivity to ferroptosis inducers (FINs). Finally, we discovered that certain FINs were able to sensitize ZVI-resistant cancer cells to become treatable without compromising healthy non-malignant cells. These findings suggest that ferroptosis can serve as a druggable target for anti-cancer nanomedicine and therapeutic resistance modulation using ZVI NPs.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ferro/farmacologia , Neoplasias Bucais/tratamento farmacológico , Nanopartículas/química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ferro/química , Neoplasias Bucais/patologia , Relação Estrutura-Atividade
6.
Biomaterials ; 34(32): 7873-83, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23876757

RESUMO

We present an approach for synchronizing hyperthermia and thermal-responsive local drug release. The targeting probe has a magnetite nanocrystal (Fe3O4@PSMA) core and a polynucleotide shell that carries 5-fluorouracil (5-FU) and anti-human epidermal growth factor receptor 2 (anti-HER2) antibody for cancer cell-specific targeting. The targeting nanocrystals play as an important role to relay the externally delivered radiofrequency energy for tumor hyperthermia. Locoregional heat then triggers a drug release from the oligonucleotide carrier as it directly damages tumor cells. Cell viability assays and pathological examinations show that this synchronization is significantly more efficacious in both in vitro and in vivo models than hyperthermia or chemotherapy alone. Prominent tumor remission in vivo was achieved through radiofrequency synchronization of hyperthermia and chemotherapy after the nanoparticle had been intravenously injected.


Assuntos
Óxido Ferroso-Férrico/química , Fluoruracila/farmacologia , Hipertermia Induzida/métodos , Nanopartículas/química , Neoplasias/terapia , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Sobrevivência Celular , Sistemas de Liberação de Medicamentos , Masculino , Camundongos Endogâmicos C3H , Neoplasias/tratamento farmacológico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
7.
PLoS One ; 8(5): e64739, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23705007

RESUMO

BACKGROUND: Most chemotherapeutic drugs for killing cancer cells are highly cytotoxic in normal cells, which limits their clinical applications. Therefore, a continuing challenge is identifying a drug that is hypersensitive to cancer cells but has minimal deleterious effects on healthy cells. The aims of this study were to evaluate the potential of 4ß-hydroxywithanolide (4ßHWE) for selectively killing cancer cells and to elucidate its related mechanisms. METHODOLOGY AND PRINCIPAL FINDINGS: Changes in survival, oxidative stress, DNA damage, and apoptosis signaling were compared between 4ßHWE-treated oral cancer (Ca9-22) and normal fibroblast (HGF-1) cells. At 24 h and 48 h, the numbers of Ca9-22 cells were substantially decreased, but the numbers of HGF-1 cells were only slightly decreased. Additionally, the IC50 values for 4ßHWE in the Ca9-22 cells were 3.6 and 1.9 µg/ml at 24 and 48 h, respectively. Time-dependent abnormal increases in ROS and dose-responsive mitochondrial depolarization can be exploited by using 4ßHWE in chemotherapies for selectively killing cancer cells. Dose-dependent DNA damage measured by comet-nuclear extract assay and flow cytometry-based γ-H2AX/propidium iodide (PI) analysis showed relatively severer damage in the Ca9-22 cells. At both low and high concentrations, 4ßHWE preferably perturbed the cell cycle in Ca9-22 cells by increasing the subG1 population and arrest of G1 or G2/M. Selective induction of apoptosis in Ca9-22 cells was further confirmed by Annexin V/PI assay, by preferential expression of phosphorylated ataxia-telangiectasia- and Rad3-related protein (p-ATR), and by cleavage of caspase 9, caspase 3, and poly ADP-ribose polymerase (PARP). CONCLUSIONS/SIGNIFICANCE: Together, the findings of this study, particularly the improved understanding of the selective killing mechanisms of 4ßHWE, can be used to improve efficiency in killing oral cancer cells during chemoprevention and therapy.


Assuntos
Apoptose , Dano ao DNA , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Physalis/química , Espécies Reativas de Oxigênio/metabolismo , Vitanolídeos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Ensaios de Seleção de Medicamentos Antitumorais , Citometria de Fluxo , Histonas/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Biológicos , Propídio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitanolídeos/farmacologia
8.
J Agric Food Chem ; 59(8): 4288-93, 2011 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-21391609

RESUMO

We evaluated the possible anticancer performance of a natural compound, goniothalamin (GTN), against human lung cancer using as a non-small cell lung cancer (NSCLC) cell line, H1299, as the model system. Cellular proliferation was significantly inhibited by GTN. Using an improved alkaline comet-nuclear extract (comet-NE) assay, GTN was found to induce a significant increase in the tail DNA. Wound healing and zymography assays showed that GTN attenuated cell migration and caused a reduction in the activity level of two major migration-associated matrix metalloproteinases, MMP-2 and MMP-9. It can be concluded that the DNA-damaging effect of GTN against lung cancer cells leads to growth inhibition as well as a depression in migration ability. Therefore, GTN has potential as a chemotherapeutic agent against lung cancer.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Pironas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Ensaio Cometa , Humanos
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