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1.
World J Surg Oncol ; 19(1): 232, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362378

RESUMO

BACKGROUND: The aim of this study is to unravel the role of Cyanidin-3-glucoside (C3G) and its potential mechanisms in lung adenocarcinoma (LUAD). METHODS: The cell clones, proliferation, apoptosis, migration, and invasion in H1299 and A549 cells were determined by colony formation assay, 5-ethynyl-20 deoxyuridine (EdU) assay, flow cytometry, and transwell assay, respectively. The expression of p53-induced gene 3 (TP53I3) was assessed and the prognostic values of TP53I3 in LUAD via the dataset from the Cancer Genome Atlas (TCGA). In addition, the mRNA and protein expressions were detected by quantitative real-time PCR (qRT-PCR) and western blot. RESULTS: C3G inhibited the proliferation, migration, and invasion of, and also promoted the apoptosis in H1299 and A549 cells. The database of TCGA showed TP53I3 was highly expressed in LUAD tissues and correlated with the poor prognosis of LUAD patients. Moreover, we also found that C3G inhibited the proliferation, migration and invasion, and promoted apoptosis in H1299 and A549 cells by downregulating TP53I3. Additionally, C3G could inhibit the activation of phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in H1299 and A549 cells by downregulating TP53I3. CONCLUSION: This study demonstrated that C3G could inhibit the proliferation, migration and invasion, and also facilitate the apoptosis through downregulating TP53I3 and inhibiting PI3K/AKT/mTOR pathway in LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Antocianinas , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
2.
Nutrients ; 13(7)2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34371964

RESUMO

The flowering plant genus Alisma, which belongs to the family Alismataceae, comprises 11 species, including Alisma orientale, Alisma canaliculatum, and Alisma plantago-aquatica. Alismatis rhizome (Ze xie in Chinese, Takusha in Japanese, and Taeksa in Korean, AR), the tubers of medicinal plants from Alisma species, have long been used to treat inflammatory diseases, hyperlipidemia, diabetes, bacterial infection, edema, oliguria, diarrhea, and dizziness. Recent evidence has demonstrated that its extract showed pharmacological activities to effectively reverse cancer-related molecular targets. In particular, triterpenes naturally isolated from AR have been found to exhibit antitumor activity. This study aimed to describe the biological activities and plausible signaling cascades of AR and its main compounds in experimental models representing cancer-related physiology and pathology. Available in vitro and in vivo studies revealed that AR extract possesses anticancer activity against various cancer cells, and the efficacy might be attributed to the cytotoxic and antimetastatic effects of its alisol compounds, such as alisol A, alisol B, and alisol B 23-acetate. Several beneficial functions of triterpenoids found in AR might be due to p38 activation and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Moreover, AR and its triterpenes inhibit the proliferation of cancer cells that are resistant to chemotherapy. Thus, AR and its triterpenes may play potential roles in tumor attack, as well as a therapeutic remedy alone and in combination with other chemotherapeutic drugs.


Assuntos
Alisma , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rizoma , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Ecotoxicol Environ Saf ; 223: 112583, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352574

RESUMO

Nickel (Ni), a widely distributed metal, is an important pollutant in the environment. Although kidney is a crucial target of Ni toxicity, information on autophagy and the potential mechanisms of Ni-induced renal toxicity are still poorly described. As we discovered, NiCl2 could induce renal damage including decrease in renal weight, renal histological alterations, and renal function injury. According to the obtained results, NiCl2 could obviously increase autophagy, which was characterized by increase of LC3 expression and decrease of p62 expression. Meanwhile, the result of ultrastructure observation showed increased autolysosomes numbers in the kidney of NiCl2-treated mice. In addition, NiCl2 increased mRNA and protein levels of autophagy flux proteins including Beclin1, Atg5, Atg12, Atg16L1, Atg7, and Atg3. Furthermore, NiCl2 induced autophagy through AMPK and PI3K/AKT/mTOR pathways which featured down-regulated expression levels of p-PI3K, p-AKT and p-mTOR and up-regulated expression levels of p-AMPK and p-ULK1. In summary, the above results indicate involvement of autophagy in renal injury induced by NiCl2, and NiCl2 induced autophagy via PI3K/AKT/mTOR and AMPK pathways in mouse kidney.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Autofagia , Rim/metabolismo , Camundongos , Níquel , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
4.
Biomolecules ; 11(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356626

RESUMO

Neurodegenerative disorders affect fifteen percent of the world's population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer's disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.


Assuntos
Doença de Alzheimer/metabolismo , Relógios Circadianos , Disfunção Cognitiva/metabolismo , Regulação da Expressão Gênica , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Sirtuína 1/genética , Sirtuína 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
5.
Medicine (Baltimore) ; 100(31): e26623, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397798

RESUMO

BACKGROUND: Cyclin F (CCNF) dysfunction has been implicated in various forms of cancer, offering a new avenue for understanding the pathogenic mechanisms underlying hepatocellular carcinoma (HCC). We aimed to evaluate the role of CCNF in HCC using publicly available data from The Cancer Genome Atlas (TCGA). METHOD: We used TCGA data and Gene Expression Omnibus (GEO) data to analyze the differential expression of CCNF between tumor and adjacent tissues and the relationship between CCNF and clinical characteristics. We compared prognosis of patients with HCC with high and low CCNF expression and constructed receiver operating characteristic (ROC) curves. In addition, we also explored the types of gene mutations in relevant groups and conducted Gene Set Enrichment Analysis (GSEA). RESULTS: The expression of CCNF in liver cancer tissues was significantly increased compared with that in adjacent tissues, and patients with high CCNF expression had a worse prognosis than those with low CCNF expression. Patients with high CCNF expression also had more somatic mutations. High expression of CCNF hampers the prognosis independently. The GSEA showed that the "http://www.gsea-msigdb.org/gsea/msigdb/cards/BIOCARTA_WNT_PATHWAY" Wnt pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/BIOCARTA_P53_PATHWAY" P53 pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_PI3K_AKT_MTOR_SIGNALING" PI3K/Akt/mTOR pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_NOTCH_SIGNALING" Notch pathway were enriched in patients with the high CCNF expression phenotype. CONCLUSION: High CCNF expression can be seen as an independent risk factor for poor survival in HCC. Its expression may serve as a target for the diagnosis and treatment of liver cancer.


Assuntos
Carcinoma Hepatocelular/genética , Ciclinas/genética , Neoplasias Hepáticas/genética , Transdução de Sinais/genética , Carcinoma Hepatocelular/metabolismo , Ciclinas/metabolismo , Bases de Dados Genéticas , Feminino , Expressão Gênica , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Receptores Notch/metabolismo , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt/genética
6.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443472

RESUMO

Feruloylacetone (FER) is a natural degradant of curcumin after heating, which structurally reserves some functional groups of curcumin. It is not as widely discussed as its original counterpart has been previously; and in this study, its anticancer efficacy is investigated. This study focuses on the suppressive effect of FER on colon cancer, as the efficacious effect of curcumin on this typical cancer type has been well evidenced. In addition, demethoxy-feruloylacetone (DFER) was applied to compare the effect that might be brought on by the structural differences of the methoxy group. It was revealed that both FER and DFER inhibited the proliferation of HCT116 cells, possibly via suppression of the phosphorylated mTOR/STAT3 pathway. Notably, FER could significantly repress both the STAT3 phosphorylation and protein levels. Furthermore, both samples showed capability of arresting HCT116 cells at the G2/M phase via the activation of p53/p21 and the upregulation of cyclin-B. In addition, ROS elevation and changes in mitochondrial membrane potential were revealed, as indicated by p-atm elevation. The apoptotic rate rose to 36.9 and 32.2% after being treated by FER and DFER, respectively. In summary, both compounds exhibited an anticancer effect, and FER showed a greater proapoptotic effect, possibly due to the presence of the methoxy group on the aromatic ring.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Curcumina/farmacologia , Mitocôndrias/efeitos dos fármacos , Estirenos/farmacologia , Antineoplásicos/química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Curcumina/química , Curcumina/metabolismo , Ciclina B1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/agonistas , Fase G2/efeitos dos fármacos , Células HCT116 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fenol/química , Fenol/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Estirenos/química , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/agonistas
7.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445664

RESUMO

The target of rapamycin (TOR) protein kinase is an atypical Ser/Thr protein kinase and evolutionally conserved among yeasts, plants, and mammals. TOR has been established as a central hub for integrating nutrient, energy, hormone, and environmental signals in all the eukaryotes. Despite the conserved functions across eukaryotes, recent research has shed light on the multifaceted roles of TOR signaling in plant-specific functional and mechanistic features. One of the most specific features is the involvement of TOR in plant photosynthesis. The recent development of tools for the functional analysis of plant TOR has helped to uncover the involvement of TOR signaling in several steps preceding photoautotrophy and maintenance of photosynthesis. Here, we present recent novel findings relating to TOR signaling and its roles in regulating plant photosynthesis, including carbon nutrient sense, light absorptions, and leaf and chloroplast development. We also provide some gaps in our understanding of TOR function in photosynthesis that need to be addressed in the future.


Assuntos
Fotossíntese/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Proteínas de Plantas/metabolismo , Plantas/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/fisiologia
8.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445242

RESUMO

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and usually lethal lung disease and it has been widely accepted that fibroblast proliferation is one of the key characteristics of IPF. Long noncoding RNAs (lncRNAs) play vital roles in the pathogenesis of many diseases. In this study, we investigated the role of lncRNA FENDRR on fibroblast proliferation. Human lung fibroblasts stably overexpressing FENDRR showed a reduced cell proliferation compared to those expressing the control vector. On the other hand, FENDRR silencing increased fibroblast proliferation. FENDRR bound serine-arginine rich splicing factor 9 (SRSF9) and inhibited the phosphorylation of p70 ribosomal S6 kinase 1 (PS6K), a downstream protein of the mammalian target of rapamycin (mTOR) signaling. Silencing SRSF9 reduced fibroblast proliferation. FENDRR reduced ß-catenin protein, but not mRNA levels. The reduction of ß-catenin protein levels in lung fibroblasts by gene silencing or chemical inhibitor decreased fibroblast proliferation. Adenovirus-mediated FENDRR transfer to the lungs of mice reduced asbestos-induced fibrotic lesions and collagen deposition. RNA sequencing of lung tissues identified 7 cell proliferation-related genes that were up-regulated by asbestos but reversed by FENDRR. In conclusion, FENDRR inhibits fibroblast proliferation and functions as an anti-fibrotic lncRNA.


Assuntos
Proliferação de Células , Fibroblastos/metabolismo , Pulmão/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Linhagem Celular , Humanos , RNA Longo não Codificante/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , beta Catenina/genética
9.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445375

RESUMO

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.


Assuntos
Depressão/psicologia , Córtex Pré-Frontal/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/metabolismo , Técnicas de Silenciamento de Genes , Ácido Glutâmico/metabolismo , Elevação dos Membros Posteriores , Masculino , Camundongos , Serotonina/metabolismo , Natação
10.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360912

RESUMO

Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this "senescence-associated secretory phenotype (SASP)" accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy-a highly regulated catabolic process-is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors.


Assuntos
Autofagia , Senescência Celular , Neoplasias/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores
11.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361780

RESUMO

Parkinson's disease is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) and the resultant loss of dopamine in the striatum. Various studies have shown that oxidative stress and neuroinflammation plays a major role in PD progression. In addition, the autophagy lysosome pathway (ALP) plays an important role in the degradation of aggregated proteins, abnormal cytoplasmic organelles and proteins for intracellular homeostasis. Dysfunction of ALP results in the accumulation of α-synuclein and the loss of dopaminergic neurons in PD. Thus, modulating ALP is becoming an appealing therapeutic intervention. In our current study, we wanted to evaluate the neuroprotective potency of noscapine in a rotenone-induced PD rat model. Rats were administered rotenone injections (2.5 mg/kg, i.p.,) daily followed by noscapine (10 mg/kg, i.p.,) for four weeks. Noscapine, an iso-qinulinin alkaloid found naturally in the Papaveraceae family, has traditionally been used in the treatment of cancer, stroke and fibrosis. However, the neuroprotective potency of noscapine has not been analyzed. Our study showed that administration of noscapine decreased the upregulation of pro-inflammatory factors, oxidative stress, and α-synuclein expression with a significant increase in antioxidant enzymes. In addition, noscapine prevented rotenone-induced activation of microglia and astrocytes. These neuroprotective mechanisms resulted in a decrease in dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Further, noscapine administration enhanced the mTOR-mediated p70S6K pathway as well as inhibited apoptosis. In addition to these mechanisms, noscapine prevented a rotenone-mediated increase in lysosomal degradation, resulting in a decrease in α-synuclein aggregation. However, further studies are needed to further develop noscapine as a potential therapeutic candidate for PD treatment.


Assuntos
Autofagia/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Noscapina/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/genética , Parte Compacta da Substância Negra/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Catalase/genética , Catalase/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Rotenona/toxicidade , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , alfa-Sinucleína/antagonistas & inibidores , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
12.
J Transl Med ; 19(1): 374, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461934

RESUMO

BACKGROUND: Ubiquitin-conjugating enzyme E2T (UBE2T) acts as an oncogene in various types of cancer. However, the mechanisms behind its oncogenic role remain unclear in lung cancer. This study aims to explore the function and clinical relevance of UBE2T in lung cancer. METHODS: Lentiviral vectors were used to mediate UBE2T depletion or overexpress UBE2T in lung cancer cells. CCK8 analysis and western blotting were performed to investigate the effects of UBE2T on proliferation, autophagy, and relevant signaling pathways. To exploit the clinical significance of UBE2T, we performed immunohistochemistry staining with an anti-UBE2T antibody on 131 NSCLC samples. Moreover, we downloaded the human lung adenocarcinoma (LUAD) dataset from The Cancer Atlas Project (TCGA). Lasso Cox regression model was adopted to establish a prognostic model with UBE2T-correlated autophagy genes. RESULTS: We found that UBE2T stimulated proliferation and autophagy, and silencing this gene abolished autophagy in lung cancer cells. As suggested by Gene set enrichment analysis, we observed that UBE2T downregulated p53 levels in A549 cells and vice versa. Blockade of p53 counteracted the inhibitory effects of UBE2T depletion on autophagy. Meanwhile, the AMPK/mTOR signaling pathway was activated during UBE2T-mediated autophagy, suggesting that UBE2T promotes autophagy via the p53/AMPK/mTOR pathway. Interestingly, UBE2T overexpression increased cisplatin-trigged autophagy and led to cisplatin resistance of A549 cells, whereas inhibiting autophagy reversed drug resistance. However, no association was observed between UEB2T and overall survival in a population of 131 resectable NSCLC patients. Therefore, we developed and validated a multiple gene signature by considering UBE2T and its relevance in autophagy in lung cancer. The risk score derived from the prognostic signature significantly stratified LUAD patients into low- and high-risk groups with different overall survival. The risk score might independently predict prognosis. Interestingly, nomogram and decision curve analysis demonstrated that the signature's prognostic accuracy culminated while combined with clinical features. Finally, the risk score showed great potential in predicting clinical chemosensitivity. CONCLUSIONS: We found that UBE2T upregulates autophagy in NSCLC cells by activating the p53/AMPK/mTOR signaling pathway. The clinical predicting ability of UBE2T in LUAD can be improved by considering the autophagy-regulatory role of UBE2T.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Proteínas Quinases Ativadas por AMP , Adenocarcinoma de Pulmão/genética , Autofagia , Humanos , Neoplasias Pulmonares/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/genética , Enzimas de Conjugação de Ubiquitina/genética
13.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371919

RESUMO

Besides its well-known psychoactive effects, caffeine has a broad range of actions. It regulates several physiological mechanisms as well as modulates both native and adaptive immune responses by various ways. Although caffeine is assumed to be a negative regulator of inflammation, the effect on the secretion of pro- and anti-inflammatory cytokines is highly controversial. Macrophages are major mediators of inflammatory responses; however, the various subpopulations develop different effects ranging from the initiation to the resolution of inflammation. Here we report a comparative analysis of the effect of caffeine on two subpopulations of human monocyte-derived macrophages differentiated in the presence of macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in M-MΦs and GM-MΦs, respectively. We showed that although TNF-α secretion was downregulated in both LPS-activated MΦ subtypes by caffeine, the secretion of IL-8, IL-6, and IL-1ß as well as the expression of Nod-like receptors was enhanced in M-MΦs, while it did not change in GM-MΦs. We showed that caffeine (1) altered adenosine receptor expression, (2) changed Akt/AMPK/mTOR signaling pathways, and (3) inhibited STAT1/IL-10 signaling axis in M-MΦs. We hypothesized that these alterations play an important modulatory role in the upregulation of NLRP3 inflammasome-mediated IL-1ß secretion in LPS-activated M-MΦs following caffeine treatment.


Assuntos
Cafeína/farmacologia , Citocinas/metabolismo , Fatores Imunológicos/farmacologia , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Células Cultivadas , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Fenótipo , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
14.
Nat Commun ; 12(1): 4852, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381028

RESUMO

Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Ubiquitina Tiolesterase/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiocinas/metabolismo , Regulação para Baixo , Humanos , Tolerância Imunológica , Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Proteína Fosfatase 2C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores
15.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207825

RESUMO

Non-clear cell renal cell carcinomas are a miscellaneous group of tumors that include different histological subtypes, each one characterized by peculiarity in terms of genetic alteration, clinical behavior, prognosis, and treatment response. Because of their low incidence and poor enrollment in clinical trials, alongside their heterogeneity, additional efforts are required to better unveil the pathogenetic mechanisms and, consequently, to improve the treatment algorithm. Nowadays, tyrosine kinase inhibitors, mTOR and MET inhibitors, and even cisplatin-based chemotherapy and immunotherapy are potential weapons that are still under evaluation in this setting. Various biomarkers have been evaluated for detecting progression and monitoring renal cell carcinoma, but more studies are necessary to improve this field. In this review, we provide an overview on the molecular characteristics of this group of tumors and the recently published trials, giving an insight into what might become the future therapeutic standard in this complex world of non-clear cell kidney cancers.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met , Serina-Treonina Quinases TOR , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
16.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209164

RESUMO

For many years, the biology of glycosphingolipids was elucidated with the help of glucosylceramide synthase (GCS) inhibitors such as 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Additionally, PDMP gained interest because of its chemosensitizing effects. Several studies have successfully combined PDMP and anti-cancer drugs in the context of cancer therapy. However, the mechanism of action of PDMP is not fully understood and seems to go beyond glycolipid inhibition. Here, we used a functionalized sphingosine analogue (pacSph) to investigate the acute effects of PDMP on cellular sphingolipid distribution and found that PDMP, but not other GCS inhibitors, such as ND-DNJ (also called Miglustat), induced sphingolipid accumulation in lysosomes. This effect could be connected to defective export from lysosome, as monitored by the prolonged lysosomal staining of sphingolipids as well as by a delay in the metabolic conversion of the pacSph precursor. Additionally, other lipids such as lysobisphosphatidic acid (LBPA) and cholesterol were enriched in lysosomes upon PDMP treatment in a time-dependent manner. We could further correlate early LBPA enrichment with dissociation of the mechanistic target of rapamycin (mTOR) from lysosomes followed by nuclear translocation of its downtream target, transcription factor EB (TFEB). Altogether, we report here a timeline of lysosomal lipid accumulation events and mTOR inactivation arising from PDMP treatment.


Assuntos
Glucosiltransferases/antagonistas & inibidores , Metabolismo dos Lipídeos/efeitos dos fármacos , Lisossomos/metabolismo , Morfolinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Glucosiltransferases/metabolismo , Células HeLa , Humanos
17.
Life Sci ; 282: 119847, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34293399

RESUMO

AIMS: Thymic carcinoma is a rare type of cancer without an established standard pharmaceutical treatment. This study investigated the antitumor effect of dimethyl itaconate (DI), a cell-permeable derivative of itaconate, on human thymic carcinoma cell line. MAIN METHODS: Human thymic carcinoma cell line Ty82 was used to evaluate the effect of DI on cell viability. Western blotting and immunohistochemistry were performed to determine the molecular mechanism of antitumor effects of DI on Ty82. KEY FINDINGS: DI suppressed cell growth and promoted apoptosis of Ty82. The suppressive effect of DI on Ty82 was mediated by the downregulation of lactate dehydrogenase A (LDHA), and the subsequent decrease in the activity of mechanistic target of rapamycin (mTOR). DI exhibited synergistic antitumor effects with a specific inhibitor of large neutral amino acid transporter 1 (LAT1), an amino acid transporter currently being investigated as a novel target for cancer therapy. SIGNIFICANCE: Our findings demonstrate that DI is a novel potential strategy for thymic carcinoma treatment.


Assuntos
Antineoplásicos/farmacologia , L-Lactato Desidrogenase/metabolismo , Proteínas de Neoplasias/metabolismo , Succinatos/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Timoma , Neoplasias do Timo , Linhagem Celular Tumoral , Humanos , Timoma/tratamento farmacológico , Timoma/enzimologia , Timoma/patologia , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/enzimologia , Neoplasias do Timo/patologia
18.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203293

RESUMO

The PI3K/mTOR signalling pathway plays a central role in the governing of cell growth, survival and metabolism. As such, it must integrate and decode information from both external and internal sources to guide efficient decision-making by the cell. To facilitate this, the pathway has evolved an intricate web of complex regulatory mechanisms and elaborate crosstalk with neighbouring signalling pathways, making it a highly non-linear system. Here, we describe the mechanistic biological details that underpin these regulatory mechanisms, covering a multitude of negative and positive feedback loops, feed-forward loops, competing protein interactions, and crosstalk with major signalling pathways. Further, we highlight the non-linear and dynamic network behaviours that arise from these regulations, uncovered through computational and experimental studies. Given the pivotal role of the PI3K/mTOR network in cellular homeostasis and its frequent dysregulation in pathologies including cancer and diabetes, a coherent and systems-level understanding of the complex regulation and consequential dynamic signalling behaviours within this network is imperative for advancing biology and development of new therapeutic approaches.


Assuntos
Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Homeostase , Humanos , Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
19.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-34223631

RESUMO

Acute myelogenous leukemia (AML) is frequently accompanied by a poor prognosis. The majority of patients with AML will experience recurrence due to multiple drug resistance. Our previous study reported that targeting the mTOR pathway may increase cell sensitivity to doxorubicin (Doxo) and provide an improved therapeutic approach to leukemia. However, the effect and mechanism of action of NVP­BEZ235 (BEZ235), a dual inhibitor of PI3K/mTOR, on Doxo­resistant K562 cells (K562/A) is yet to be elucidated. Therefore, the aim of the present study was to investigate the effects of BEZ235 on K562/A cell proliferation. K562/A cells was investigated using CCK­8, flow cytometry and western blotting, following BEZ235 treatment. It was observed that BEZ235 significantly decreased the viability of K562/A cells. In addition, BEZ235 arrested K562/A cells at the G0/G1 phase, and reduced the protein expression levels of CDK4, CDK6 and cyclin D1. Apoptotic cells were more frequently detected in K562/A cells treated with BEZ235 compared with the control group (12.97±0.91% vs. 7.37±0.42%, respectively; P<0.05). Cells treated with BEZ235 exhibited downregulation of Bcl­2 and upregulation of Bax. Furthermore, BEZ235 treatment markedly decreased the activation of the PI3K/AKT/mTOR pathway and its downstream effectors. Thus, these results demonstrated that BEZ235 inhibited cell viability, induced G0/G1 arrest and increased apoptosis in K562/A cells, suggesting that BEZ235 may reverse Doxo resistance in leukemia cells. Therefore, targeting the PI3K/mTOR pathway may be of value as a novel therapeutic approach to leukemia.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imidazóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Quinolinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Fase G1/efeitos dos fármacos , Humanos , Células K562 , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
20.
Life Sci ; 283: 119840, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34298040

RESUMO

AIMS: The high glycolysis state of tumor cells is closely related to radioresistance. Fructose-1,6-bisphosphatase (FBP1) can regulate aerobic glycolysis and exerts tumor suppressor effects in many cancers, but its role in nasopharyngeal carcinoma (NPC) remains to be investigated. MATERIALS AND METHODS: RT-qPCR was used to measure FBP1 mRNA level. Glucose consumption, lactic acid production and ATP level was determined to evaluate glycolysis. The sensitivity of NPC cells to radiation was analyzed by MTT assay. Apoptosis was performed using flow cytometry. Gain- and loss-of function assays were carried out to explore the specific role of FBP1 and FBXW7 (F-box and WD repeat domain-containing 7) in NPC cell functions. The interactions between FBXW7 and FBP1 or mTOR were validated with co-immunoprecipitation assay. The in vivo experiments with xenografts were used to evaluate the role of FBP1 in tumor growth. KEY FINDINGS: FBP1 expression was lower in NPC tissues and cells than in normal controls and nasopharyngeal epithelial cells. Human recombinant FBP1 (rh-FBP1) treatment suppressed glycolysis in NPC cells. Besides, silencing FBP1 weakened the radiosensitivity and alleviated radiation-induced apoptosis and DNA damage by promoting glycolysis. Mechanism exploration found that FBP1 promoted FBXW7 protein level through suppressing the autoubiquitination of FBXW7. Then, FBXW7 restrained mTOR level by facilitating mTOR ubiquitination, thereby suppressing glycolysis and promoting radiation-induced apoptosis and DNA damage. Furthermore, overexpressing FBP1 in vivo hindered tumor growth and enhanced the antitumor activity of radiation. SIGNIFICANCE: FBP1 promoted the radiosensitivity in NPC cells by inhibiting glycolysis through the FBXW7/mTOR axis.


Assuntos
Proteína 7 com Repetições F-Box-WD/metabolismo , Glicólise , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular Tumoral , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Frutose-Bifosfatase/genética , Frutose-Bifosfatase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Proteínas de Neoplasias/genética , Serina-Treonina Quinases TOR/genética
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