Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 467
Filtrar
1.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321903

RESUMO

The fibroblast growth factor (FGF) signaling cascade is one of the key signaling pathways in hepatocellular carcinoma (HCC). FGF has been shown to augment vascular endothelial growth factor (VEGF)-mediated HCC development and angiogenesis, as well as to potentially lead to resistance to VEGF/VEGF receptor (VEGFR)-targeted agents. Thus, novel agents targeting FGF/FGF receptor (FGFR) signaling may enhance and/or overcome de novo or acquired resistance to VEGF-targeted agents in HCC. Mice bearing high- and low-FGFR tumors were treated with Infigratinib (i.e., a pan-FGFR kinase inhibitor) and/or Bevacizumab (i.e., an angiogenesis inhibitor). The antitumor activity of both agents was assessed individually or in combination. Tumor vasculature, intratumoral hypoxia, and downstream targets of FGFR signaling pathways were also investigated. Infigratinib, when combined with Bevacizumab, exerted a synergistic inhibitory effect on tumor growth, invasion, and lung metastasis, and it significantly improved the overall survival of mice bearing FGFR-dependent HCC. Infigratinib/Bevacizumab promoted apoptosis, inhibited cell proliferation concomitant with upregulation of p27, and reduction in the expression of FGFR2-4, p-FRS-2, p-ERK1/2, p-p70S6K/4EBP1, Cdc25C, survivin, p-Cdc2, and p-Rb. Combining Infigratinib/Bevacizumab may provide therapeutic benefits for a subpopulation of HCC patients with FGFR-dependent tumors. A high level of FGFR-2/3 may serve as a potential biomarker for patient selection to Infigratinib/Bevacizumab.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inibidores da Angiogênese/administração & dosagem , Animais , Antineoplásicos Imunológicos/administração & dosagem , Apoptose , Bevacizumab/administração & dosagem , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos SCID , Metástase Neoplásica , Compostos de Fenilureia/administração & dosagem , Pirimidinas/administração & dosagem , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Survivina/genética , Survivina/metabolismo , Hipóxia Tumoral , Fosfatases cdc25/genética , Fosfatases cdc25/metabolismo
2.
Anticancer Res ; 40(10): 5417-5421, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988862

RESUMO

BACKGROUND: Type II diabetes agents have anticancer effects on head and neck squamous cell carcinoma (HNSCC). The mechanistic target of rapamycin (MTOR) pathway represents a putative target. MATERIALS AND METHODS: We interrogated an Affymetrix HNSCC dataset for MTOR-related gene expression. RESULTS: MTOR expression itself was unchanged, but various related genes demonstrated differential expression. Pathway promoters ras homolog (RHEB), MTOR-associated protein (MLST8), and ribosomal protein S6 kinase B1 (RPS6KB1) were up-regulated. Expression of growth suppressors tuberous sclerosis complex 2 (TSC2), programmed cell death 4 (PDCD4), and BCL2 apoptosis regulator-associated agonist of cell death (BAD) were reduced in HNSCC. Upstream, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT serine/threonine kinase 1 (AKT1), and phosphatase and tensin homolog (PTEN) were up-regulated in cancer. CONCLUSION: Several MTOR pathway promoters and tumor suppressors were found to be differentially expressed, favoring MTOR pathway up-regulation in HNSCC. Genomic databases can be interrogated to identify intervention targets and endpoints in HNSCC trials.


Assuntos
Bases de Dados Genéticas , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Neoplasias/genética , Serina-Treonina Quinases TOR/genética , Proteínas Reguladoras de Apoptose/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/patologia , Humanos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas de Ligação a RNA/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína de Morte Celular Associada a bcl/genética , Homólogo LST8 da Proteína Associada a mTOR/genética
3.
Gene ; 757: 144943, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32652105

RESUMO

The growth of animal skeletal muscle is mainly determined by the synthesis processes of total proteins in skeletal muscle cells, which has a significant impact on the postnatal growth of young animals. An increasing number of studies are focusing on the functions of Tuberous sclerosis complex 2 (TSC2) during the process of cell protein synthesis and growth. However, it is still unclear the effect of whether and how TSC2 on goat myoblasts proliferation and differentiation. Here, we found that TSC2 gene has opposite expression patterns in proliferation and differentiation of myoblasts. An expression vector containing goat TSC2 cDNA sequences linked with pcDNA3.1 plasmid was constructed. Myoblasts proliferation activity was significantly inhibited and cell cycle transition slowed down after the transfection of pcDNA3.1-TSC2 plasmid into goat primary myoblasts by EdU staining, CCK-8 and flow cytometry. Mechanically, we further confirmed that the overexpression TSC2 was able to down-regulate the mRNA and protein expression of mechanistic target of rapamycin (mTOR), p70 ribosomal S6 kinase 1 (p70S6K) and some cell cycle related genes. In addition, the expression of myogenic genes and myotube formation were attenuated. Collectively, all our results of the experiment demonstrate that TSC2 could regulate myoblasts cells proliferation and differentiation via the activation of the mTOR/p70S6K signaling pathway.


Assuntos
Diferenciação Celular , Proliferação de Células , Desenvolvimento Muscular , Mioblastos/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Cabras , Mioblastos/citologia , Mioblastos/fisiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Regulação para Cima
4.
Am J Obstet Gynecol ; 223(5): 753.e1-753.e14, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32416155

RESUMO

BACKGROUND: Autophagy is highly active in neuroepithelial cells of the developing neuroepithelium, and impairment of autophagy leads to neural tube defects. In this study, we have found that maternal diabetes suppresses autophagy that leads to neural tube defects and consequent cellular imbalance in the endoplasmic reticulum where critical events occur, leading to the induction of diabetic embryopathy. Because the mammalian target of rapamycin pathway suppresses autophagy, we hypothesized that 70 kDa ribosomal protein S6 kinase 1 (p70S6K1), a major downstream effector of mammalian target of rapamycin, mediates the inhibitory effect of maternal diabetes on autophagy in the developing neuroepithelium. OBJECTIVE: We investigated whether p70S6K1 mediates the inhibitory effect of maternal diabetes on autophagy during neurulation. We also examined whether p70S6K1 deficiency restores autophagy and therefore relieves endoplasmic reticulum stress and inhibits maternal diabetes-induced apoptosis, which leads to reduction in neural tube defect incidence in diabetic embryopathy. STUDY DESIGN: Female p70S6K1 heterogeneous knockout (p70S6K1+/-) mice were bred with male p70S6K1 heterogeneous knockout (p70S6K1+/-) mice to generate wild-type (WT), p70S6K1+/- and p70S6K1 knockout (p70S6K1-/-) embryos. Embryos at embryonic day 8.5 were harvested for the assessment of indices of autophagy, endoplasmic reticulum stress, and apoptosis. Neural tube defect incidence in embryos was determined at embryonic day 10.5. For in vitro studies, small interfering RNA knockdown of p70S6K1 in C17.2 mouse neural stem cells was used to determine the effect of p70S6K1 deficiency on autophagy impairment and endoplasmic reticulum stress under high glucose conditions. RESULTS: Knockout of the Rps6kb1 gene, which encodes for p70S6K1, ameliorated maternal diabetes-induced NTDs and restored autophagosome formation in neuroepithelial cells suppressed by maternal diabetes. Maternal diabetes-suppressed conversion of LC3-I (microtubule-associated protein 1A/1B-light chain 3) to LC3-II, an index of autophagic activity, in neurulation stage embryos was abrogated in the absence of p70S6K1. p70S6K1 knockdown in neural stem cells also restored autophagosome formation and the conversion of LC3-I to LC3-II. The activation of the major unfolded protein response, indicated by phosphorylation of inositol-requiring enzyme 1 alpha, and protein kinase R-like endoplasmic reticulum kinase, and eukaryotic translation initiation factor 2α, and the increase of the endoplasmic reticulum stress marker, C/EBP homologous protein, were induced by maternal diabetes in vivo and high glucose in vitro. Unfolded protein response and endoplasmic reticulum stress induced by maternal diabetes or high glucose were reduced by Rps6kb1 deletion or p70S6K1 knockdown, respectively. Rps6kb1 knockout blocked maternal diabetes-induced caspase cleavage and neuroepithelial cell apoptosis. The superoxide dismutase mimetic Tempol abolished high glucose-induced p70S6K1 activation. CONCLUSION: The study revealed the critical involvement of p70S6K1 in the pathogenesis of diabetic embryopathy.


Assuntos
Autofagia/genética , Estresse do Retículo Endoplasmático/genética , Doenças Fetais/genética , Células-Tronco Neurais/metabolismo , Defeitos do Tubo Neural/genética , Gravidez em Diabéticas/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Resposta a Proteínas não Dobradas/genética , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Glicemia/metabolismo , Óxidos N-Cíclicos/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Doenças Fetais/etiologia , Doenças Fetais/metabolismo , Glucose/farmacologia , Técnicas In Vitro , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/metabolismo , Células Neuroepiteliais/efeitos dos fármacos , Células Neuroepiteliais/metabolismo , Neurulação/genética , Estresse Oxidativo , Gravidez , Gravidez em Diabéticas/metabolismo , Marcadores de Spin , Resposta a Proteínas não Dobradas/efeitos dos fármacos
5.
J Virol ; 94(12)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32295907

RESUMO

Mumps virus (MuV) caused the most viral meningitis before mass immunization. Unfortunately, MuV has reemerged in the United States in the past several years. MuV is a member of the genus Rubulavirus, in the family Paramyxoviridae, and has a nonsegmented negative-strand RNA genome. The viral RNA-dependent RNA polymerase (vRdRp) of MuV consists of the large protein (L) and the phosphoprotein (P), while the nucleocapsid protein (NP) encapsulates the viral RNA genome. These proteins make up the replication and transcription machinery of MuV. The P protein is phosphorylated by host kinases, and its phosphorylation is important for its function. In this study, we performed a large-scale small interfering RNA (siRNA) screen targeting host kinases that regulated MuV replication. The human kinase ribosomal protein S6 kinase beta-1 (RPS6KB1) was shown to play a role in MuV replication and transcription. We have validated the role of RPS6KB1 in regulating MuV using siRNA knockdown, an inhibitor, and RPS6KB1 knockout cells. We found that MuV grows better in cells lacking RPS6KB1, indicating that it downregulates viral growth. Furthermore, we detected an interaction between the MuV P protein and RPS6KB1, suggesting that RPS6KB1 directly regulates MuV replication and transcription.IMPORTANCE Mumps virus is an important human pathogen. In recent years, MuV has reemerged in the United State, with outbreaks occurring in young adults who have been vaccinated. Our work provides insight into a previously unknown mumps virus-host interaction. RPS6KB1 negatively regulates MuV replication, likely through its interaction with the P protein. Understanding virus-host interactions can lead to novel antiviral drugs and enhanced vaccine production.


Assuntos
Genoma Viral , Vírus da Caxumba/genética , Proteínas do Nucleocapsídeo/genética , Fosfoproteínas/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Virais/genética , Animais , Chlorocebus aethiops , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Interações Hospedeiro-Patógeno/genética , Humanos , Vírus da Caxumba/metabolismo , Proteínas do Nucleocapsídeo/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Ligação Proteica , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Células Vero , Proteínas Virais/metabolismo , Replicação Viral
6.
Clin Sci (Lond) ; 134(6): 609-628, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32175563

RESUMO

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague-Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-ß (TGF-ß) levels. The effects of RXRα down-regulation by RXRα small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.


Assuntos
Bexaroteno/administração & dosagem , Cardiomiopatias/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Proteínas Serina-Treonina Quinases/metabolismo , Receptores X Retinoide/agonistas , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Sprague-Dawley , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Estreptozocina
7.
Oncol Rep ; 43(3): 886-896, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020217

RESUMO

Osteosarcoma is one of the most malignant bone tumors, and its major threats are aggressive invasion and early tumor metastasis, which result in a poor prognosis and high mortality. Accumulating evidence indicates that ginsenoside compound K (CK) has a significant antitumor effect, particularly on the inhibition of proliferation and invasion of numerous human tumors. In the present study, it was revealed that CK inhibited the viability and proliferation of osteosarcoma cells. Moreover, it was demonstrated that CK induced apoptosis and inhibited the migration and invasion of osteosarcoma cells via apoptotic staining, Annexin V/PI staining, and Transwell invasion assays. Furthermore, at the molecular level, the present results confirmed that apoptosis and invasion­related proteins were regulated by CK, which was possibly related to the blockade of the PI3K/mTOR/p70S6K1 signaling pathway. In summary, the present findings indicated that CK inhibited viability and proliferation, induced apoptosis, and inhibited the migration and invasion of osteosarcoma cells through the PI3K/mTOR/p70S6K1 signaling pathway.


Assuntos
Ginsenosídeos/farmacologia , Osteossarcoma/tratamento farmacológico , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Serina-Treonina Quinases TOR/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/genética , Osteossarcoma/patologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
8.
J Cell Biol ; 219(3)2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32040547

RESUMO

Cell proliferation exerts a high demand on protein synthesis, yet the mechanisms coupling the two processes are not fully understood. A kinase and phosphatase screen for activators of translation, based on the formation of stress granules in human cells, revealed cell cycle-associated kinases as major candidates. CDK1 was identified as a positive regulator of global translation, and cell synchronization experiments showed that this is an extramitotic function of CDK1. Different pathways including eIF2α, 4EBP, and S6K1 signaling contribute to controlling global translation downstream of CDK1. Moreover, Ribo-Seq analysis uncovered that CDK1 exerts a particularly strong effect on the translation of 5'TOP mRNAs, which includes mRNAs encoding ribosomal proteins and several translation factors. This effect requires the 5'TOP mRNA-binding protein LARP1, concurrent to our finding that LARP1 phosphorylation is strongly dependent on CDK1. Thus, CDK1 provides a direct means to couple cell proliferation with biosynthesis of the translation machinery and the rate of protein synthesis.


Assuntos
Proteína Quinase CDC2/metabolismo , Proliferação de Células , Neoplasias do Colo do Útero/enzimologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Autoantígenos/genética , Autoantígenos/metabolismo , Proteína Quinase CDC2/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fatores de Iniciação em Eucariotos/genética , Fatores de Iniciação em Eucariotos/metabolismo , Feminino , Fibroblastos/enzimologia , Regulação Enzimológica da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Cinética , Camundongos Endogâmicos C57BL , Fosforilação , Biossíntese de Proteínas , Sequência de Oligopirimidina na Região 5' Terminal do RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
9.
Oxid Med Cell Longev ; 2020: 5363546, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064026

RESUMO

The present study was performed to evaluate the antioxidant and intestinal protective effects of baicalin-copper on deoxynivalenol-challenged piglets. Forty weaned piglets were randomly divided into four groups and assigned to different diets: (1) basal diet (Con), (2) 4 mg/kg deoxynivalenol of basal diet (DON), (3) 5 g/kg baicalin-copper of basal diet (BCU); and (4) 4 mg/kg deoxynivalenol + 5 g/kg baicalin-copper of basal diet (DBCU). The results showed that the ADFI and ADG of piglets in the DON group were markedly lower than those in the Con group, but the ADFI and ADG of the DBCU group were not significantly different from those of the Con group. In piglets fed a DON-contaminated diet, dietary supplementation with BCU significantly decreased the mRNA levels of P70S6K, 4E-BP1, and HSP70 in the liver, the protein expression of HO-1 in the jejunum, and the expression of p-Nrf2 and p-NF-κB in the ileum but increased Mn-SOD activity in serum. Dietary supplementation with BCU increased jejunal maltase, ZIP4 and MT mRNA levels, and serum concentrations of Arg, Val, Ile, Leu, Lys, and Tyr in DON-contaminated piglets. In summary, BCU can alleviate the growth impairment induced by DON and enhance antioxidant capacity and nutrition absorption in piglets fed DON-contaminated diets.


Assuntos
Antioxidantes/metabolismo , Flavonoides/farmacologia , Íleo/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tricotecenos/toxicidade , Aminoácidos/sangue , Ração Animal , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobre/química , Dieta , Suplementos Nutricionais , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Íleo/metabolismo , Jejuno/citologia , Jejuno/enzimologia , Jejuno/metabolismo , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Soro/enzimologia , Soro/metabolismo , Superóxido Dismutase-1/sangue , Suínos , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
10.
Int J Mol Sci ; 21(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32054043

RESUMO

The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ativação Enzimática , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Mapas de Interação de Proteínas , Proteínas Quinases S6 Ribossômicas 70-kDa/análise , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Serina-Treonina Quinases TOR/análise , Serina-Treonina Quinases TOR/genética
11.
Sci Rep ; 10(1): 641, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959810

RESUMO

Emerging evidence suggests that the mammalian target of rapamcyin (mTOR) pathway is associated with radio-resistance in cancer treatment. We hypothesised that phosphorylated ribosomal S6 kinase 1 (p-S6K1), a major downstream regulator of the mTOR pathway, may play a role in predicting radio-resistance. Therefore, we evaluated the association of p-S6K1 expression with radio-resistance in breast cancer cell lines and patients. During median follow-up of 33 (range, 0.1-111) months for 1770 primary breast cancer patients who underwent surgery, patients expressing p-S6K1 showed worse 10-year loco-regional recurrence-free survival (LRFS) compared to that of p-S6K1-negative patients after radiotherapy (93.4% vs. 97.7%, p = 0.015). Multivariate analysis revealed p-S6K1 expression as a predictor of radio-resistance (hazard ratio 7.9, 95% confidence interval 1.1-58.5, p = 0.04). In vitro, CD44high/CD24low MCF7 cells with a radioresistant phenotype expressed higher levels of p-S6K1 than control MCF7 cells. Furthermore, the combination of radiation with treatment of everolimus, an mTOR-S6K1 pathway inhibitor, sensitised CD44high/CD24low MCF7 cells to a greater extent than MCF7 cells. This study provides in vivo and in vitro evidence for p-S6K1 expression status as an important marker for predicting the resistance to radiotherapy and as a possible target for radio-sensitization in breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Expressão Gênica , Estudos de Associação Genética , Tolerância a Radiação/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Feminino , Seguimentos , Previsões , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento
12.
Chem Biol Interact ; 317: 108943, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926917

RESUMO

Epidemiological studies have shown that cigarette smoking is beneficial in ulcerative colitis and that nicotine may be responsible for this effect. However, the mechanism remains unclear. In a previous study, nicotine was found to induce autophagy in intestinal cells. Here, we evaluated the effect of nicotine-induced autophagy in a dextran sodium sulfate (DSS)-induced colitis mouse model. C57BL/6 adult male mice drank DSS water solution freely for seven consecutive days, and then tap water was administered. The effect of nicotine treatment was examined in the DSS model, including colon length, disease severity, histology of the colon tissue, and inflammation levels. Moreover, autophagy levels were detected by Western blot analysis (LC3II/LC3I, p62, and beclin-1). The levels of DSS-induced colitis were significantly decreased following nicotine treatment. The disease activity score, body weight, histologic damage scores, and the level of colonic inflammatory factors of nicotine-treated mice all decreased compared to those of the control mice. Additionally, nicotine enhanced the expression of LC3II/LC3I and beclin-1 but decreased the p62 protein level. Inhibiting autophagy by 3-MA attenuated the protective effects of nicotine on colitis. Additionally, both in vitro and in vivo experiments showed changes in AMPK-mTOR-P70S6K during this process. These results suggest that nicotine improved colitis by regulating autophagy and provided a protective effect against DSS-induced colitis.


Assuntos
Adenilato Quinase/metabolismo , Autofagia/efeitos dos fármacos , Colite/prevenção & controle , Nicotina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenilato Quinase/genética , Animais , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/genética
13.
J Cell Physiol ; 235(2): 1247-1258, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31267531

RESUMO

It is well known that the acquisition of chemoresistance is a major obstacle for the effective treatment of human cancers. It is reported that microRNAs (miRNAs) are implicated in chemotherapy resistance of various malignancies. miR-10b was previously proved as an oncogene in multiple malignancies, including esophageal cancer. However, its biological significance in regulating cisplatin (DDP) resistance in esophageal cancer is still elusive. Here, we observed that miR-10b expression was upregulated and peroxisome proliferator-activated receptor-γ (PPARγ) expression was downregulated in esophageal cancer tumor tissues and cells. PPARγ was proved as a functional target of miR-10b. Moreover, suppression of miR-10b enhanced the chemosensitivity of esophageal cancer cells to DDP in vitro and in vivo. In addition, PPARγ-mediated DDP sensitivity was weakened by miR-10b overexpression. Furthermore, miR-10b-activated AKT/mTOR/p70S6K signaling pathway through targeting PPARγ. Inactivation of AKT/mTOR/p70S6K by AKT inhibitor (GSK690693) attenuated miR-10b-induced DDP resistance in esophageal cancer cells. Taken together these observation, miRNA-10b-mediated PPARγ inhibition enhanced DDP resistance by activating the AKT/mTOR/P70S6K signaling in esophageal cancer, suggesting a potential target to improve therapeutic response of patients with esophageal cancer to DDP.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Experimentais , PPAR gama/genética , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/genética
14.
Mol Cell Biochem ; 463(1-2): 13-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31541353

RESUMO

Insulin stimulates de novo lipid synthesis in the liver and in cultured hepatocytes via its ability to activate sterol regulatory element-binding protein 1c (SREBP-1c). Although PI3K-AKT-mTORC1-p70S6K-signaling kinases are known to drive feed-forward expression of SREBP-1c, the identity of the phosphorylated amino acid residue(s) putatively involved in insulin-stimulated de novo lipogenesis remains elusive. We obtained in silico and mass spectrometry evidence, that was combined with siRNA strategies, to discover that insulin-induced phosphorylation of serine 418, serine 419, and serine 422 in rat SREBP-1c was most likely mediated by p70S6 kinase. Here, for the first time, we show that insulin-induced phosphorylation of these 3 serine residues mainly impinged on the mechanisms of proteostasis of both full-length and mature SREBP-1c in the McArdle-RH7777 hepatoma cells. Consistent with this conclusion, nascent SREBP-1c, substituted with phosphomimetic aspartic acid residues at these 3 sites, was resistant to proteasomal degradation. As a consequence, endoplasmic reticulum to Golgi migration and proteolytic maturation of pSREBP-1c was significantly enhanced which led to increased accumulation of mature nSREBP-1c, even in the absence of insulin. Remarkably, aspartic acid substitutions at S418, S419 and S422 also protected the nascent SREBP-1c from ubiquitin-mediated proteasome degradation thus increasing its steady-state levels and transactivation potential in the nucleus. These complementary effects of p70S6K-mediated phosphorylation on proteostasis of pSREBP-1c were necessary and sufficient to account for insulin's ability to enhance transcription of genes controlling de novo lipogenesis in hepatocytes.


Assuntos
Hepatócitos/metabolismo , Lipídeos/biossíntese , Lipogênese , Proteostase , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Hepatócitos/citologia , Humanos , Lipídeos/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Serina-Treonina Quinases TOR/genética , Transcrição Genética
15.
J Cell Physiol ; 235(2): 1065-1075, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31264208

RESUMO

Chronic high-fat-diet (HFD) consumption can lead to the development of brain insulin resistance, which then exerts deleterious effects on learning and memory. Activity-regulated cytoskeleton-associated protein (Arc) is a memory-related protein, and its expression can be induced by insulin stimulation. In HFD-fed animals, their basal Arc protein levels in cerebral cortex and hippocampus are reduced. However, the effects of HFD on novelty-induced Arc protein expression that is important for cognitive function is still unknown. In the present study, after feeding HFD (60% kcal from fat) for 5 weeks, mice developed brain insulin resistance and had a significant reduction in the novelty-induced but not the basal Arc protein levels in their hippocampi. Further experiments were performed in primary rat hippocampal neurons. The results show that, under the condition of neuronal insulin resistance, acute insulin stimulation induced less activation of the phosphatidylinositol 3-kinase/protein kinase B/p70 ribosomal S6 kinase (PI3K/Akt/p70S6K) pathway, resulting in reduced induction of Arc protein expression. Accordingly, it is suggested that following HFD feeding, the reduction in novelty-induced Arc protein expression in animal's hippocampus is probably related to a suppressed activation of the PI3K/Akt/p70S6K pathway due to the existence of brain insulin resistance.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Dieta Hiperlipídica , Gorduras na Dieta/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Ração Animal/análise , Animais , Células Cultivadas , Proteínas do Citoesqueleto/genética , Hipocampo/citologia , Insulina/farmacologia , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
16.
J Diabetes Investig ; 11(1): 39-51, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31199578

RESUMO

AIMS/INTRODUCTION: Although increased reactive oxygen species (ROS) generation is a major mechanism leading to cardiac remodeling in diabetes mellitus, research into the effects of anti-oxidation on diabetic cardiac remodeling remains scarce and controversial. Glucagon-like peptide-1 (GLP-1) shows potential anti-oxidative effects besides lowering blood glucose. The objective of this research was to investigate the effects of GLP-1 on cardiac remodeling and the molecular mechanism involved in diabetes mellitus. MATERIALS AND METHODS: Streptozotocin-induced diabetic rats received exenatide treatment for 3 months. Cardiac function, cardiac weight index and myocardial interstitial fibrosis were measured. Cardiomyocytes were cultured in high-glucose medium with GLP-1 treatment. The ROS production, apoptosis and the levels of mammalian target of rapamycin complex 1/p70 ribosomal protein S6 kinase protein expression in cardiomyocytes were analyzed. RESULTS: Experimental diabetes mellitus showed impaired cardiac diastolic function, increased brain natriuretic peptide expression and increased interstitial collagen deposition in the myocardium, which were ameliorated by exenatide treatment. Exenatide reduced myocardial ROS production and apoptosis in diabetes mellitus. Also, high glucose-induced ROS generation and apoptosis in cardiomyocytes were inhibited by GLP-1, as well as the levels of mammalian target of rapamycin complex 1/p70 ribosomal protein S6 kinase phosphorylation. Furthermore, GLP-1 treatment upregulated adenosine monophosphate-activated protein kinase activity in high-glucose-induced cardiomyocyte. CONCLUSIONS: Glucagon-like peptide-1 protects the cardiomyocytes from oxidative stress and apoptosis in diabetes mellitus, which might contribute to the improvement of cardiac remodeling. The cardiac protection of GLP-1 might be dependent on inhibition of mammalian target of rapamycin complex 1/p70 ribosomal protein S6 kinase, through an adenosine monophosphate-activated protein kinase-mediated pathway.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Exenatida/farmacologia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Hipoglicemiantes/farmacologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais
17.
J Anim Physiol Anim Nutr (Berl) ; 104(1): 300-309, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31674084

RESUMO

Excessive protein levels in diets result in incomplete digestion of nitrogenous nutrients that are excreted from the body, causing environment pollution. Alpha-ketoglutarate (AKG) has been reported to decrease dietary protein levels, promote intestinal health in piglets and reduce environmental pollution. However, the underlying mechanisms of AKG are largely unknown. The objective of this study was to determine the effects of low-protein diet supplementation of AKG on the growth performance, nitrogen metabolism, relative expression of amino acid transporter genes and mTOR signalling pathway of skeletal muscle in piglets. Forty-eight piglets with an initial weight of 11.53 ± 0.04 kg were randomly divided into four groups. Each group had four replicates, and each replicate had three pigs. A low-protein (LP) diet (crude protein was 14.96%) served as the control without AKG, while 0.5%, 1.0% and 1.5% AKG were added to the LP diet for the other experimental groups. The trial period lasted for 28 days. Compared with the LP group, the LP + 1.0%A and LP + 1.5%A groups increased the growth performance (p < .05);increased the mRNA levels of amino acid transporters in the duodenum, anterior jejunum and posterior jejunum (p < .05); and reduced faecal nitrogen and urine nitrogen emissions (p < .05). They also showed greater mRNA levels and phosphorylated protein levels for S6 kinase beta (S6K) (p < .05), mammalian target of rapamycin (mTOR) (p < .05) and 4E-binding protein 1 (4EBP1) (p < .05) in skeletal muscle. An LP diet supplemented with AKG activated the mTOR signalling and promoted the ability of the small intestine to absorb protein, thereby increasing protein deposition. Taken together, an LP diet supplemented with AKG provides a theoretical basis for the promotion and application of AKG in piglet production.


Assuntos
Dieta com Restrição de Proteínas/veterinária , Ácidos Cetoglutáricos/farmacologia , Nitrogênio/metabolismo , Suínos/crescimento & desenvolvimento , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Ácidos Cetoglutáricos/administração & dosagem , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/genética
18.
Mol Cell Biochem ; 465(1-2): 13-26, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31782083

RESUMO

Cellular signals that influence Cap-dependent translation have assumed significant relevance in the backdrop of their enforced dysregulation during oncogenesis. Eukaryotic initiation factor 4E(eIF4E), the mRNA cap-binding protein, has emerged as a key player to facilitate tumor progression through upregulated cap-dependent translation synchronized with enhanced cell division. We provide evidence that eIF4E phosphorylation is regulated by mTORC1 by virtue of its interaction with Raptor through a novel TPTPNPP motif and consequent phosphorylation invitro and in vivo in a Rapamycin-sensitive manner. While we show that phosphorylation pattern of eIF4E responds faithfully to Rapamycin inhibition, the prolonged exposure to Rapamycin rescues the loss of eIF4E phosphorylation through Mnk1 activation. We also present evidence that eIF4E interacts with the amino terminal domain of S6K1 in a phospho-dependent manner, and this interaction is instrumental in overriding Rapamycin inhibition of S6K1. The data endorses eIF4E as a regulatory subunit that modulates the functional attributes of mTOR effectors to synchronize cap-dependent translation with growth assertion.


Assuntos
Fator de Iniciação 4E em Eucariotos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Motivos de Aminoácidos , Animais , Fator de Iniciação 4E em Eucariotos/genética , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Células NIH 3T3 , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteínas Serina-Treonina Quinases/genética , Proteína Regulatória Associada a mTOR/genética , Proteína Regulatória Associada a mTOR/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Sirolimo/farmacologia
19.
Int J Oncol ; 56(1): 327-336, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31789385

RESUMO

The long non­coding RNA colon cancer­associated transcript 2 (CCAT2) is abnormally expressed in various types of malignant tumor tissues and considered to be an oncogene, including for esophageal cancer (EC). Radiotherapy is an important and widely used cancer treatment. However, some patients with EC do not respond to radiotherapy. This study was designed to investigate effects of CCAT2 expression on radiotherapy dynamics for EC cells and to explore underlying molecular mechanisms. Reverse transcription­quantitative PCR was used to measure CCAT2 expression in EC tissues, normal esophageal mucosa, EC cells and normal human esophageal epithelial cells. TUNEL assays were used to assess the effect of CCAT2 on X­ray­induced apoptosis of EC cells. Protein expression was detected by western blot. CCAT2 was highly expressed in EC tissues and EC cells, and was negatively associated with radiotherapy efficacy in patients with EC. In vitro, knockdown of CCAT2 enhanced radiosensitivity of EC cells and promoted apoptosis by increasing Bax/Bcl2 and active­caspase 3/caspase 3 following X­ray treatment. In addition, CCAT2 negatively regulated miR­145 and P70 ribosomal protein S6 kinase 1 (p70S6K1) expression, and inhibited phosphorylation of Akt, ERK and p70S6K1 in EC cells. After X­ray treatment, CCAT2 negatively regulated protein levels of p53, P21 and c­Myc. These results showed that CCAT2 promoted the radiotherapy resistance of EC cells via negative regulation of the miR­145/p70S6K1 and the p53 signaling pathways and associated elements may be potential targets for improving the sensitivity of EC radiotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Tolerância a Radiação/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Biosci Rep ; 39(12)2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31799599

RESUMO

PD-L1 is a well-known immune co-stimulatory molecule that regulates tumour cell escape from immunity by suppressing the immune response. However, the clinical significance of PD-L1 in the progression of ovarian cancer is unclear. Our study demonstrated that PD-L1 is up-regulated in ovarian tumour tissue compared with its expression level in adjacent normal tissue. Furthermore, we confirmed that PD-L1 increases the proliferation of cancer cells by activating the AKT-mTORC signalling pathway, which is also enhanced by the expression of S6K, the substrate of mTORC. In addition, PD-L1 promotes the autophagy of ovarian cancer cells by up-regulating the expression of BECN1, a crucial molecule involved in the regulation of autophagy. In conclusion, PD-L1 may provide a target for the development of a novel strategy for the treatment of ovarian cancer.


Assuntos
Autofagia/genética , Antígeno B7-H1/genética , Carcinogênese/genética , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Interferon gama/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...