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1.
J Agric Food Chem ; 67(39): 10871-10879, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31517482

RESUMO

This study evaluated the effect of triterpenoids from edible mushroom Poria cocos on intestinal epithelium integrity and revealed the transcriptional regulatory pathways that underpin restorative mechanisms in the gut. Based on computational docking studies, transcriptional activation experiments and glucocorticoid receptor (GR) protein immunofluorescence localization assays in cultured cells, 16α-hydroxytrametenolic acid (HTA) was discovered as a novel GR agonist in this study. HTA ameliorates TNF-α-induced Caco-2 monolayer intestinal epithelial barrier damage and suppressed activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), which attenuated downstream IκB and nuclear factor kappa-B (NF-κB) phosphorylation through GR activation. Moreover, HTA prevented NF-κB translocation into the nucleus and binding to its cis-element and suppressed lipopolysaccharide-induced downstream NO production and pro-inflammatory cytokines at both protein and mRNA expression levels. In conclusion, HTA from P. cocos improves intestinal barrier function through a GR-mediated PI3K/Akt/NF-κB signaling pathway and may be potentially exploited as a supportive dietary therapeutic strategy for restoring gut health.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Glucocorticoides/metabolismo , Triterpenos/farmacologia , Wolfiporia/química , Células CACO-2 , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Mucosa Intestinal/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/genética , Fosfatidilinositol 3-Quinase/genética , Fosforilação , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Glucocorticoides/genética , Transdução de Sinais/efeitos dos fármacos , Triterpenos/química , Verduras/química
2.
J Agric Food Chem ; 67(42): 11657-11664, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31549821

RESUMO

The therapeutic benefits of whole grains on diabetes mellitus have been continuously confirmed by in-depth research. To date, limited studies have investigated the effect of extruded products of whole grains on the insulin signaling pathway in vivo. This study investigated the effects of oral consumption of whole grain extrudate, including 97% brown rice and 3% defatted rice bran (w/w, BRD), on glucose metabolism and the hepatic insulin signaling pathway in C57BL/KsJ-db/db mice. BRD treatment induced a remarkable reduction in blood glucose. Moreover, glucose intolerance and insulin resistance were ameliorated in the BRD-treated group compared with those in the db/db control group. BRD also increased the hepatic glycogen content by reducing the expression and increasing the phosphorylation of glycogen synthase kinase 3ß (GSK3ß). The activities of glucose-6-phosphatase and phosphoenolpyruvate carboxylase and their respective mRNA expression levels in the liver were simultaneously decreased in the BRD-treated group. BRD also significantly upregulated the expression of phosphatidylinositol 3-kinase (PI3K) and increased the phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (AKT). These results indicate that BRD exhibits antidiabetic potential by activating the IRS1/PI3K/AKT signaling pathway, further regulating the expression of the FOXO1 gene and p-GSK3ß protein, thus inhibiting hepatic gluconeogenesis, increasing hepatic glycogen storage, and improving insulin resistance. Therefore, BRD could be used as a functional ingredient to alleviate the symptoms of hyperglycemia.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Oryza/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Teste de Tolerância a Glucose , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Oryza/química , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
3.
J Agric Food Chem ; 67(20): 5754-5763, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31045365

RESUMO

Recently, although ginseng ( Panax ginseng C. A. Meyer) and its main component saponins (ginsenosides) have been reported to exert protective effects on cisplatin (CDDP)-induced acute kidney injury (AKI), the beneficial activities of non-saponin on CDDP-induced AKI is little known. This research was designed to explore the protective effect and underlying mechanism of arginyl-fructosyl-glucose (AFG), a major and representative non-saponin component generated during the process of red ginseng, on CDDP-caused AKI. AFG at doses of 40 and 80 mg/kg remarkably reversed CDDP-induced renal dysfunction, accompanied by the decreased levels of serum creatinine and blood urea nitrogen. Interestingly, all of oxidative stress indices were ameliorated after pretreatment with AFG continuously for 10 days. Importantly, AFG relieved CDDP-induced inflammation and apoptosis in part by mitigating the cascade initiation steps of nuclear factor κB signals and regulating the participation of the phosphatidylinositol 3-kinase/protein kinase B signal pathway. In conclusion, these results clearly provide strong rationale for the development of AFG to prevent CDDP-induced AKI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Arginina/análogos & derivados , Cisplatino/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Glucose/administração & dosagem , Glicina/análogos & derivados , NF-kappa B/metabolismo , Panax/química , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Arginina/administração & dosagem , Arginina/química , Creatinina/metabolismo , Medicamentos de Ervas Chinesas/química , Glucose/química , Glicina/administração & dosagem , Glicina/química , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Reação de Maillard , Masculino , Camundongos Endogâmicos ICR , NF-kappa B/genética , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
4.
Mol Med Rep ; 19(6): 4673-4684, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957185

RESUMO

Non­alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and has high rates of morbidity and mortality worldwide. Daphnetin (DAP) possesses notable antioxidative, anti­inflammatory and anticoagulant activities; DAP is an active ingredient extracted from Daphne Koreana Nakai. To investigate the effects and the underlying mechanism of DAP on NAFLD, we treated HepG2 cells with oleic acid (OA) and DAP simultaneously and non­simultaneously. In the simultaneous treatment condition, HepG2 cells were co­treated with 0.5 mM OA and DAP (5, 20, and 50 µM) for 24 h. In the non­simultaneous treatment conditions, HepG2 cells were pretreated with 0.5 mM OA for 24 h, and then treated with DAP (5, 20 and 50 µM) for 24 h. Following the aforementioned treatments, the biochemical indexes associated with NAFLD were measured as follows: i) The intracellular contents of triglyceride (TG), reactive oxygen species (ROS) and fluorescent glucose 2­[N­(7­nitrobenz­2­oxa­1,3­diazol­4­yl) amino]­2­deoxyglucose were analyzed with corresponding detection kits; and ii) the cellular expression levels of glycolipid metabolism­ and oxidative stress­related genes, including 5'AMP­activated protein kinase (AMPK), sterol regulatory element­binding protein­1C (SREBP­1C), patatin­like phospholipase domain­containing protein 3 (PNPLA3), peroxisome proliferator­activated receptor α (PPARα), phosphoinositide 3­kinase (PI3K), protein kinase B (AKT), nuclear factor­like 2 (Nrf2), cytochrome P450 (CYP) 2E1 and CYP4A were determined by reverse transcription­quantitative polymerase chain reaction and western blotting. The results revealed the potential mechanism underlying the effects of DAP on NAFLD in vitro: i) By increasing the phosphorylation of AMPK, DAP inhibited the expression of SREBP­1C and PNPLA3, and induced that of PPARα. Lipid accumulation within hepatocytes was reduced; ii) by upregulating PI3K expression and pAKT/AKT levels, DAP may alleviate insulin resistance and promote hepatocellular glucose uptake; and iii) by upregulating the expression of Nrf2, DAP downregulated the expression of CYP2E1 and CYP4A, and the levels of reactive oxygen species in hepatocytes.


Assuntos
Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácido Oleico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Umbeliferonas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP4A/genética , Citocromo P-450 CYP4A/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Lipase/antagonistas & inibidores , Lipase/genética , Lipase/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR alfa/genética , PPAR alfa/metabolismo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
5.
Oncol Rep ; 41(6): 3499-3507, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002344

RESUMO

Non­small cell lung carcinomas (NSCLC) are common and are the leading cause of cancer­associated mortality worldwide. Heptadecanoic acid (C17:0) is an odd­chain saturated fatty acid. The effect of C17:0 on lung cancer has remained elusive. The present study examined the role of C17:0 in the PC­9 NSCLC cell line and PC­9 cells with acquired­gefitinib resistance (PC­9/GR) in vitro. Cell proliferation, migration, apoptosis, fatty acid composition and the activation of relevant signaling pathways were assessed. The results indicated that C17:0 significantly inhibited cell proliferation, and migration, while promoting apoptosis in PC­9 and PC­9/GR cells. Furthermore, C17:0 enhanced the cytotoxicity of gefitinib to PC­9 and PC­9/GR cells. Mechanistical analysis indicated that the activation of the phosphoinositide 3­kinase/Akt signaling pathway was suppressed in C17:0­treated PC­9 and PC­9/GR cells. Furthermore, the addition of C17:0 led to accumulation of 10­cis­heptadecenoic acid in NSCLC cells. Collectively, the present study demonstrated that C17:0 is an effective agent against NSCLC cells in vitro and the results may imply that the intake of C17:1 or C17:0­rich food may be beneficial during the treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/farmacologia , Gefitinibe/efeitos adversos , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinase/genética , Transdução de Sinais/efeitos dos fármacos
6.
Life Sci ; 224: 95-108, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905782

RESUMO

AIMS: Parkinson's disease (PD) is a common neurodegenerative disease typically associated with the accumulation of α-synuclein. Autophagy impairment is thought to be involved in the dopaminergic neurodegeneration in PD. We investigate the effect of Apelin-36 on the activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/the mammalian target of rapamycin (mTOR) autophagy pathway in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells, which is involved in the cytoprotective effect of Apelin-36. MAIN METHODS: SH-SY5Y cells were treated with 1-Methyl-4-phenylpyridine (MPP+) with or without Apelin-36. The cell viability, apoptotic ratio, the form of autophagic vacuoles, the expression of tyrosine hydroxylase (TH), α-synuclein, phosphorylation of PI3K, AKT, mTOR, microtubule-associated protein 1 Light Chain 3 II/I (LC3II/I) and p62 were detected to investigate the neuroprotective effect of Apelin-36. KEY FINDINGS: The results indicate that Apelin-36 significantly improved the cell viability and decreased the apoptosis in MPP+-treated SH-SY5Y cells. The decreased expression of tyrosine hydroxylase (TH) induced by MPP+ was significantly increased by Apelin36 pretreatment. Moreover, Apelin36 significantly increased the autophagic vacuoles. The ratio of LC3II/I was significantly increased by Apelin36, as well as the decreased p62 expression. In addition, the activated PI3K/AKT/mTOR pathway induced by MPP+ was significantly inhibited by Apelin36. Additionally, Apelin36 significantly decreased the α-synuclein expression. Furthermore, the cytoprotective effect of Apelin-36 was weakened by pretreatment with Insulin-like Growth Factor-1 (IGF-1), an activator of PI3K/Akt, and MHY1485, an mTOR activator. SIGNIFICANCE: Our results demonstrated that Apelin-36 protects against MPP+-induced cytotoxicity through PI3K/Akt/mTOR autophagy pathway in PD model in vitro, which provides a new theoretical basis for the treatment of PD.


Assuntos
1-Metil-4-fenilpiridínio/efeitos adversos , Apelina/metabolismo , Neuroblastoma/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Apelina/genética , Apoptose , Autofagia , Humanos , Neuroblastoma/induzido quimicamente , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fosfatidilinositol 3-Quinase/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Células Tumorais Cultivadas
7.
J Physiol Biochem ; 75(1): 19-28, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30729392

RESUMO

Diabetes mellitus significantly hampers the development of cardioprotective response to remote pre/post/perconditioning stimuli by impairing the activation of cardioprotective signaling pathways. Among the different pathways, the impairment in O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling and release of cardioprotective humoral factor may contribute in attenuating remote preconditioning-induced cardioprotection. Moreover, the failure to phosphorylate extracellular signal related kinase (ERK), phosphoinositide-3-kinase (PI3K), and AKT along with up-regulation of mechanistic target of rapamycin (mTOR) and decrease in autophagy may also attenuate remote preconditioning-induced cardioprotection. Remote perconditioning stimulus also fails to phosphorylate AKT kinase in diabetic heart. In addition, diabetes may increase the oxidative stress, reactive oxygen species (ROS) production, decrease the beclin expression, and inhibit autophagy to attenuate remote perconditioning-induced cardioprotection. Moreover, diabetes-induced increase in the Rho-associated kinase (ROCK) activity, decrease in the arginase activity, and reduction in nitric oxide (NO) bioavailability may also contribute in decreasing remote perconditioning-induced cardioprotection. Diabetes may reduce the phosphorylation of adenosine 5'-monophosphate activated protein kinase (AMPKα) and increase the phosphorylation of mTOR to attenuate cardioprotection of remote postconditioning. The present review describes the role of diabetes in attenuating remote ischemic conditioning-induced cardioprotection along with the possible mechanisms.


Assuntos
Acetilglucosamina/metabolismo , Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica , Precondicionamento Isquêmico Miocárdico , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/terapia , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Autofagia , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
8.
Fish Shellfish Immunol ; 87: 705-713, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30668999

RESUMO

A full-length cDNA encoding phosphatidylinositol 3-kinase regulatory subunit gamma b gene in Nile tilapia (Oreochromis niloticus), termed as On-pik3r3b, was identified and characterized in this study. The sequence analysis demonstrated that the full-length cDNA of On-pik3r3b was 2018 bp, containing a 5' untranslated region (UTR) of 171 bp, an open reading frame (ORF) of 1422 bp and a 3' UTR of 425 bp. Its protein sequence displayed a high degree of identity with other fish. Using qPCR, the expression patterns of On-pik3r3b were investigated. In healthy Nile tilapia, the transcripts of On-pik3r3b were detected in all examined tissues, except the skin. Upon the stimulation with Streptococcus agalactiae, the On-pik3r3b expression level in liver, spleen, kidney and gill were significantly increased at 12 h after infection. The recombinant On-pik3r3b showed in vitro antibacterial activity, against S. agalactiae and E. coli. Our observation strongly indicates that On-pik3r3b is involved in the innate immune response in Nile tilapia.


Assuntos
Ciclídeos/genética , Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Fosfatidilinositol 3-Quinase/química , Filogenia , Alinhamento de Sequência/veterinária
9.
Oncol Rep ; 41(1): 570-578, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30365150

RESUMO

Thyroid cancer is the most commonly diagnosed malignancy of the endocrine system, the incidence of which has increased rapidly in the last 30 years. Genetic alterations in pathways, including the mitogen­activated protein kinase (MAPK)/extracellular signal­regulated kinase (Erk) and phosphatidylinositol­3­kinase (PI3K)/protein kinase B (Akt) pathways, are the driving force behind the development of differentiated thyroid cancer cases into aggressive and undifferentiated forms of thyroid cancer. E26 transformation (ETS)­specific related transcription factor­3 (ELF3) belong to the epithelial­specific subfamily of ETS transcription factors and has recently been reported to be involved in various pathophysiological processes. However, the role of ELF3 in thyroid cancer has not yet been investigated. In the present study, data from The Cancer Genome Atlas (TCGA) were analyzed, and it was revealed that ELF3 was overexpressed in patients with papillary thyroid cancer (PTC). Furthermore, the expression of ELF3 was found to be higher in thyroid cancer tissues with a B­Raf proto­oncogene (BRAF) mutation as determined by western blot analysis and IHC staining. Additionally, ELF3 overexpression predicted a poor prognosis in patients with PTC. The MAPK signaling pathway inhibitor PLX4032 was demonstrated to strongly attenuate ELF3 protein levels in BRAF­mutant thyroid cancer cell lines. Knockdown of ELF3 with small interfering RNA (siRNA) inhibited the growth, clone formation, migration and invasion of BRAF mutant thyroid cancer cells. Mechanistically, ELF3 modulated the activity of the MAPK/Erk pathway via transcriptional regulation of the human epidermal growth factor receptor 2 family of receptors as determined by RT­qPCR. In conclusion, the present study demonstrated ELF3 to be a potential prognostic marker for patients with thyroid cancer. Notably, ELF3 was demonstrated to form a positive feedback loop with MAPK pathways leading to the progression of BRAF­mutant thyroid cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Proto-Oncogênicas c-ets/genética , Transdução de Sinais/genética , Neoplasias da Glândula Tireoide/genética , Fatores de Transcrição/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fosfatidilinositol 3-Quinase/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Receptor ErbB-2/genética , Neoplasias da Glândula Tireoide/patologia , Transcrição Genética/genética
10.
Mol Med Rep ; 19(2): 1024-1031, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569107

RESUMO

Diabetic retinopathy (DR) is a retinal disease caused by metabolic disorders of glucose tolerance that can lead to irreversible blindness if not adequately treated. Retinal pigment epithelial cell (RPEC) dysfunction contributes to the pathogenesis of DR. In the present study the anti­inflammatory effect of curcumin (CUR) was investigated in RPECs damaged by high glucose levels. RPEC treated with 30 mmol/l glucose was regarded as high glucose group, and cells treated with 24.4 mmol/l mannitol was set as equivalent osmolarity group. Cell Counting Kit­8 assay was used to measure RPEC viability, the expression of phosphorylated (p)­AKT and p­mammalian target of rapamycin (mTOR) were assessed by western blot, and secretion of tumor necrosis factor (TNF)­α, interleukin (IL)­6 and IL­1ß in the culture medium was measured by ELISA. Intracellular reactive oxygen species (ROS) levels were measured by laser scanning confocal microscope. The present data indicated that, compared with mannitol treatment, high glucose treatment reduced RPEC viability, increased TNF­α, IL­6 and IL­1ß secretion, increased ROS formation and promoted phosphorylation of AKT and mTOR. The antioxidant N­acetylcysteine, the phosphoinositide 3­kinase (PI3K)/AKT inhibitor LY294002 and the mTOR inhibitor rapamycin ameliorated the effects of high glucose. In addition, pretreatment with 10 µmol/l CUR reduced secretion levels of TNF­α, IL­6 and IL­1ß, ROS formation and phosphorylation of AKT and mTOR. In conclusion, CUR inhibited high glucose­induced inflammatory injury in RPECs by interfering with the ROS/PI3K/AKT/mTOR signaling pathway. The present study may reveal the molecular mechanism of CUR inhibition effects to high glucose­induced inflammatory injury in RPEC.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/farmacologia , Células Epiteliais/efeitos dos fármacos , Glucose/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Cromonas/farmacologia , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Sinergismo Farmacológico , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Glucose/toxicidade , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Modelos Biológicos , Morfolinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Int J Mol Sci ; 19(12)2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30544563

RESUMO

The phosphoinositide 3-kinase (PI3K) signalling pathway is highly dysregulated in cancer, leading to elevated PI3K signalling and altered cellular processes that contribute to tumour development. The pathway is normally orchestrated by class I PI3K enzymes and negatively regulated by the phosphatase and tensin homologue, PTEN. Endometrial carcinomas harbour frequent alterations in components of the pathway, including changes in gene copy number and mutations, in particular in the oncogene PIK3CA, the gene encoding the PI3K catalytic subunit p110α, and the tumour suppressor PTEN. PIK3CB, encoding the other ubiquitously expressed class I isoform p110ß, is less frequently altered but the few mutations identified to date are oncogenic. This isoform has received more research interest in recent years, particularly since PTEN-deficient tumours were found to be reliant on p110ß activity to sustain transformation. In this review, we describe the current understanding of the common and distinct biochemical properties of the p110α and p110ß isoforms, summarise their mutations and highlight how they are targeted in clinical trials in endometrial cancer.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias do Endométrio/genética , Feminino , Humanos , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinase/genética
12.
Elife ; 72018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30560783

RESUMO

Although it has been known for over a decade that the inflammatory mediator NGF sensitizes pain-receptor neurons through increased trafficking of TRPV1 channels to the plasma membrane, the mechanism by which this occurs remains mysterious. NGF activates phosphoinositide 3-kinase (PI3K), the enzyme that generates PI(3,4)P2 and PIP3, and PI3K activity is required for sensitization. One tantalizing hint came from the finding that the N-terminal region of TRPV1 interacts directly with PI3K. Using two-color total internal reflection fluorescence microscopy, we show that TRPV1 potentiates NGF-induced PI3K activity. A soluble TRPV1 fragment corresponding to the N-terminal Ankyrin repeats domain (ARD) was sufficient to produce this potentiation, indicating that allosteric regulation was involved. Further, other TRPV channels with conserved ARDs also potentiated NGF-induced PI3K activity. Our data demonstrate a novel reciprocal regulation of PI3K signaling by the ARD of TRPV channels.


Assuntos
Membrana Celular/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Animais , Linhagem Celular , Membrana Celular/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células Híbridas , Camundongos , Microscopia de Fluorescência/métodos , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositóis/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
13.
Neurol Res ; 40(12): 1014-1020, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30156477

RESUMO

OBJECTIVE: The aim of this study was to evaluate the potential molecular mechanism of resveratrol (RSV) that attenuates brain damage from focal cerebral ischemia. METHODS AND MATERIALS: To investigate whether phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway was involved in RSV anti-inflammatory and neuroprotective properties. Middle cerebral artery occlusion (MCAO) animal model was used in this study. Adult male Sprague-Dawley (SD) rats underwent MCAO, and then received treatment with RSV or vehicle after the onset of ischemia. PI3K inhibitor LY294002 was injected intracerebroventricularly to inhibit the PI3K/Akt signaling pathway. Neurological deficit scores and cerebral water content were assessed 24 h after MCAO. The inflammatory factors interleukin (IL)-1ß, tumor necrosis factor (TNFα), and cyclooxygenase-2 (COX2) mRNA level were examined by real-time PCR. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after MCAO. The protein expression of phospho-Akt and COX2 in ischemic brain were determined by western blot. RESULTS: RSV significantly reduced neurological deficit scores, cerebral water content and the enzymatic activity of MPO, all of which were abolished by LY294002 administration. Real-time PCR showed that RSV significantly suppressed the upregulation of the inflammatory factors IL-1ß, TNFα, COX2 mRNA levels. RSV significantly inhibited upregulated the protein expression of COX2 24 h after MCAO, which effect was abolished by LY294002 administration. CONCLUSION: RSV attenuated ischemic brain damage induced by cerebral artery occlusion mainly through PI3K/Akt signaling pathway. Abbreviation: MCAO: Middle cerebral artery occlusion; RSV: resveratrol; PI3K/Akt: phosphatidylinositol 3-kinase/Akt; TNF: tumor necrosis factor; COX2: cyclooxygenase-2; MPO: myeloperoxidase; IL: interleukin.


Assuntos
Antioxidantes/uso terapêutico , Isquemia Encefálica/complicações , Hipóxia Encefálica/tratamento farmacológico , Hipóxia Encefálica/etiologia , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico , Análise de Variância , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Masculino , Exame Neurológico , Proteína Oncogênica v-akt/genética , Proteína Oncogênica v-akt/metabolismo , Peroxidase/metabolismo , Fosfatidilinositol 3-Quinase/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Resveratrol
14.
Clin. transl. oncol. (Print) ; 20(8): 1035-1045, ago. 2018. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-173687

RESUMO

Background: To investigate the effect of CXCL12 gene silencing on proliferation,invasion, angiogenesis and the relationship of MAPK/PI3K/AP-1 signaling pathway in colon cancer cells. Methods: RT-PCR and Western-blot were used to detect the expression of CXCL12 mRNA and protein in four colon cancer cell lines. Human colon cancer cells were transfected with CXCL12 siRNA carrying by Lipofectamine 2000. The expression of CXCL12 protein was confirmed by immunoblotting. WST-1, invasion and angiogenesis assay were used to examine the effect on proliferation, invasion and angiogenesis in colon cancer cells after CXCL12 siRNA silence, respectively. The phosphorylation of MAPK/PI3K/AP-1 protein levels was detected by Western blotting in CXCL12 siRNA suppression DLD-1 cell. Results: CXCL12 mRNA and proteins were only expressed in DLD-1 colon cancer cell lines. CXCL12 siRNA were transfected into DLD-1 cells, the expression CXCL12 proteins was significantly inhibited (P < 0.01), and the proliferation, invasion and angiogenesis of DLD-1 cells were inhibited significantly (P < 0.01). CXCL12 gene silencing resulted in blockage of MAPK, PI3K and AP-1 phosphorylation by CXCL12-induced in DLD-1 colon cancer cell. Conclusion: The silencing CXCL12 gene significantly inhibits the proliferation, invasion and angiogenesis ability of some types colon carcinoma cells through down-regulation of MAPK/PI3K/AP-1 signaling pathway


No disponible


Assuntos
Humanos , Quimiocina CXCL12/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Fosfatidilinositol 3-Quinase/genética , Neoplasias do Colo/genética , Fator de Transcrição AP-1/genética , Metástase Neoplásica/genética , Transdução de Sinais/genética , Invasividade Neoplásica/genética , Marcadores Genéticos/genética
15.
Med Sci Monit ; 24: 4592-4601, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29969438

RESUMO

BACKGROUND The aim of this study was to explore the potential effects of long noncoding RNA (lncRNA) LINC003121 on thyroid cancer (TC) cell proliferation and invasion and to explore their possible mechanisms with the involvement of the PI3K/Akt signaling pathway. MATERIAL AND METHODS We enrolled 211 thyroid cancer tissues and 70 adjacent normal tissues in this study. TC cell lines K1, SW579, and 8505C and the human thyroid follicular cell line Nthy-ori3-1 were selected and assigned into blank, control vectors, LINC00312 vectors, si-control, and si-LINC00312 groups. Quantitative real-time PCR was used to determine the levels of LINC003121 and Western blotting was used to detect the protein expression of MMP-9, PI3K, t-Akt, and p-Akt. Cell proliferation was assessed by CCK8 assay and EdU incorporation assay, and cell invasion was assessed by Transwell assay. RESULTS The expression of LINC00312 was significantly decreased in TC tissues and cell lines. In an in vitro experiment, si-LINC00312 significantly promoted the invasion and proliferation of TC cells. Conversely, overexpression of LINC00312 decreased cell proliferation and invasion in vitro, and decreased tumorigenicity in TC xenograft models in nude mice. LINC00312-mediated tumor suppression in TC cells may occur via suppression of activation of the PI3K/Akt signaling pathway and expression of MMP-9, and the role of MMP-9 expression induced by overexpressed LINC00312 or si-LINC00312 could be weakened by LY294002 (PI3K inhibitor). CONCLUSIONS LINC00312 can act as a tumor-suppressor in TC by attenuating the PI3K/Akt signaling pathway, and LINC00312 could be a novel diagnosis biomarker and a promising therapeutic target for TC patients.


Assuntos
Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , RNA Longo não Codificante/administração & dosagem , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/terapia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Mol Med Rep ; 18(3): 2798-2806, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30015881

RESUMO

Endothelial cell autophagy has a protective role in inhibiting inflammation and preventing the development of atherosclerosis, which may be regulated by microRNA (miR)­155. The present study aimed to investigate the mechanisms of autophagy in the development of atherosclerosis. Human umbilical vein endothelial cells model in vitro and using oxidized low­density lipoprotein (ox­LDL) stimulated cells to simulate the atherosclerosis. MiR­155 mimics, miR­155 inhibitors, and a negative control were respectively transfected in human umbilical vein endothelial cells to analyzed alterations in the expression of miR­155. It was demonstrated that overexpression of miR­155 promoted autophagic activity in oxidized low­density lipoprotein­stimulated human umbilical vein endothelial cells, whereas inhibition of the expression of miR­155 reduced autophagic activity. Overexpression of miR­155 revealed that it regulated autophagy via the phosphatidylinositol­3 kinase (PI3K)/RAC­α serine/threonine­protein kinase (Akt)/mechanistic target of rapamycin pathway (mTOR) signaling pathway. A luciferase reporter assay demonstrated that miR­155 directly bound to the PI3K catalytic subunit a and Ras homolog enriched in brain 3'­untranslated region and inhibited its luciferase activity. Therefore, the results of the present study suggested that miR­155 promoted autophagy in vascular endothelial cells and that this may have occurred via targeting of the PI3K/Akt/mTOR pathway. Thus, miR­155 may be considered as a potential therapeutic target for the treatment of atherosclerosis.


Assuntos
Autofagia/efeitos dos fármacos , Lipoproteínas LDL/toxicidade , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Sequência de Bases , Células Endoteliais da Veia Umbilical Humana , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fosfatidilinositol 3-Quinase/química , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/química , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Alinhamento de Sequência , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética
17.
Int J Mol Med ; 41(6): 3167-3174, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29512686

RESUMO

Gastric cancer (GC) is the second most common cause of cancer-related deaths. In recent years some essential factors for resolution were identified, but the clinical trials still lack the effective methods to treat or monitor the disease progression. Regenerating islet-derived 3α (REG3A) is a member of REG protein family. Previous studies have investigated the altered expression of REG3A in various cancers. In this investigtion we aimed at the biological function and the underlying molecular mechanism of REG3A in GC. We found that REG3A was significantly downregulated in GC and closely related with patient prognoses. REG3A overexpression suppressed the invasion and proliferation promoting apoptosis of GC cells. While REG3A knockdown promoted the invasion, and proliferation suppressing apoptosis of GC cells. It was further found that REG3A performed its biological functions mainly through phosphatidylinositol 3 kinase (PI3K)/Akt-GSK3ß signaling pathway axis. REG3A may be a promising therapeutic strategy for GC.


Assuntos
Proteínas Associadas a Pancreatite/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Apoptose/genética , Apoptose/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Humanos , Técnicas In Vitro , Proteínas Associadas a Pancreatite/genética , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
18.
Biofactors ; 44(2): 180-191, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29399897

RESUMO

In many developed countries including Japan, how to care the bedridden elderly people with chronic wounds such as decubitus becomes one of the most concerned issues. Although antioxidant micronutrients including vitamin E, especially α-tocopherol (α-Toc), are reported to shorten a period of wound closure, the promoting effect of α-Toc on wound healing independent of its antioxidant activity remains to be fully elucidated. The aim of this study was to examine whether α-Toc affects wound-mediated HaCaT keratinocyte polarization process including the recruitment of polarity regulating proteins, leading to wound repair independently of its antioxidant activity. We investigated the effects of α-Toc and other antioxidants such as Trolox, a cell-permeable α-Toc analog on the migration, proliferation, and cell polarization of HaCaT keratinocytes after wounding. We analyzed the localization and complex formation of polarity proteins, partitioning defective 3 (Par3), and atypical protein kinase C (aPKC), and aPKC activity by immunohistochemistry, immunoprecipitation analyses, and in vitro kinase assays, respectively. α-Toc but not other antioxidants enhanced the wound closure and cell polarization in HaCaT keratinocytes after wounding. α-Toc regulated the localization and complex formation of Par3 and aPKC during wound healing. Knockdown of aPKC or Par3 abrogated α-Toc-mediated promotion of the wound closure and cell polarization in HaCaT keratinocytes. Furthermore, aPKC kinase activity was significantly increased in α-Toc-treated cells through activation of phosphatidylinositol 3-kinase/Akt signaling pathway. These results suggest that α-Toc promotes HaCaT keratinocyte wound repair by regulating the aPKC kinase activity and the formation of aPKC-Par3 complex. © 2017 BioFactors, 44(2):180-191, 2018.


Assuntos
Movimento Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , alfa-Tocoferol/farmacologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Transformada , Polaridade Celular/genética , Proliferação de Células/efeitos dos fármacos , Cromanos/farmacologia , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Biológicos , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Cicatrização/efeitos dos fármacos , Cicatrização/genética
19.
Cell Signal ; 42: 44-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28951244

RESUMO

Glomerular mesangial cell hypertrophy contributes to the complications of diabetic nephropathy. The mechanism by which high glucose induces mesangial cell hypertrophy is poorly understood. Here we explored the role of the platelet-derived growth factor receptor-ß (PDGFRß) tyrosine kinase in driving the high glucose-induced mesangial cell hypertrophy. We show that high glucose stimulates the association of the PDGFRß with PI 3 kinase leading to tyrosine phosphorylation of the latter. High glucose-induced Akt kinase activation was also dependent upon PDGFRß and its tyrosine phosphorylation at 740/751 residues. Inhibition of PDGFRß activity, its downregulation and expression of its phospho-deficient (Y740/751F) mutant inhibited mesangial cell hypertrophy by high glucose. Interestingly, expression of constitutively active Akt reversed this inhibition, indicating a role of Akt kinase downstream of PDGFRß phosphorylation in this process. The transcription factor Hif1α is a target of Akt kinase. siRNAs against Hif1α inhibited the high glucose-induced mesangial cell hypertrophy. In contrast, increased expression of Hif1α induced hypertrophy similar to high glucose. We found that inhibition of PDGFRß and expression of PDGFRß Y740/751F mutant significantly inhibited the high glucose-induced expression of Hif1α. Importantly, expression of Hif1α countered the inhibition of mesangial cell hypertrophy induced by siPDGFRß or PDGFRß Y740/751F mutant. Finally, we show that high glucose-stimulated PDGFRß tyrosine phosphorylation at 740/751 residues and the tyrosine kinase activity of the receptor regulate the transforming growth factor-ß (TGFß) expression by Hif1α. Thus we define the cell surface PDGFRß as a major link between high glucose and its effectors Hif1α and TGFß for induction of diabetic mesangial cell hypertrophy.


Assuntos
Glucose/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células Mesangiais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Transformador beta/genética , Tirosina/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Mutação , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação/efeitos dos fármacos , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
20.
Oncol Rep ; 39(3): 1034-1042, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29286125

RESUMO

Gonadotropins, including luteinizing hormone (LH) and follicle stimulating hormone (FSH), are conducive to the growth of ovarian cancer based on the 'gonadotropin theory' and are regulated by gonadotropin-releasing hormone (GnRH). The present study was carried out to investigate the effect of goserelin, a GnRH agonist, on the apoptosis of epithelial ovarian cancer (EOC) cells and the underlying in vitro and in vivo mechanisms. Through flow cytometry, Hoechst staining and TUNEL staining, we demonstrated that goserelin promoted the apoptosis of EOC cells both in vitro and in vivo. Through human apoptosis gene PCR array, we verified that the promotion of EOC cell apoptosis by goserelin was linked to the upregulation of members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, which have been identified as downstream targets of forkhead box O1 (FOXO1). Goserelin enhanced FOXO1 expression, and siRNA-mediated knockdown of FOXO1 abrogated the induction of apoptosis by goserelin. Moreover, goserelin decreased AKT activity, and FOXO1 upregulation by goserelin was dependent on the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In vivo, the expression of key factors in the PI3K/AKT/FOXO1 pathway was consistent with that observed in vitro. In conclusion, our data suggested that goserelin may promote EOC cell apoptosis by upregulating FOXO1 through the PI3K/AKT signaling pathway. We believe that GnRH agonists may be potential antitumor agents, and key factors in the PI3K/AKT-FOXO1 pathway may also be novel therapeutic targets for the treatment of EOC.


Assuntos
Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Proteína Forkhead Box O1/metabolismo , Gosserrelina/farmacologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antineoplásicos Hormonais/farmacologia , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário , Proliferação de Células/efeitos dos fármacos , Feminino , Proteína Forkhead Box O1/genética , Humanos , Camundongos , Camundongos Nus , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Fosfatidilinositol 3-Quinase/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
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