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1.
2.
Int J Mol Med ; 45(4): 1187-1194, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32124954

RESUMO

Chronic myeloid leukemia (CML) is a myeloproliferative disorder that accounts for ~10% of all newly diagnosed leukemia cases. Early diagnosis is essential for long­term beneficial outcomes. The present study observed that interferon­induced protein with tetratricopeptde repeats 2 (IFIT2) expression levels were reduced in bone marrow samples from CML patients compared with control samples using RNA sequencing and reverse transcription­PCR. IFIT2 expression levels were restored in patients treated with tyrosine kinase inhibitors. To investigate the effect of IFIT2 on CML patients, a stable IFIT2 expressing K562 cell line was established. It was demonstrated that IFIT2 overexpression in K562 cells inhibits cell proliferation and arrests the cell cycle at the G1 phase. In addition, it was demonstrated by western blotting that IFIT2 inhibits the BCR­ABL oncoprotein and regulates its downstream AKT/mTOR signaling pathway. IFIT2 could induce cell cycle arrest­associated gene p27kip1 by degrading cullin1­mediated E3 ligases. In summary, the present study demonstrated that IFIT2 was efficacious in inhibiting CML and is a potential therapeutic target.

3.
Cell Signal ; 69: 109543, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31958511

RESUMO

The gene trim7 encodes at least four isoforms Glycogenin-interacting protein 1 (GNIP1), GNIP2, GNIP3 and Tripartite motif containing 7 (TRIM7). GNIP1, the longest isoform, has been reported acting as an oncogene. However, it is very interesting that TRIM7, the shortest isoform, only 15 amino acids different from GNIP1 in C-terminal, acts in a completely different way from that of GNIP1 in our present study. TRIM7 expression was decreased in tumor compared with adjacent normal tissues, and the level of TRIM7 was negatively correlated with clinical stage of 94 patients with lung cancer. In vitro, TRIM7 dramatically inhibited the proliferation and migration of tumor cells, and promoted cell apoptosis. Further study showed that TRIM7 interacted with p65 via its C-terminal which is different from GNIP1. The interaction between TRIM7 and p65 promoted the ubiquitination of p65 and finally accelerated the degradation of p65 via 26S proteasome. In vivo, the tumor volume and weight were decreased by TRIM7 stable expression. Meanwhile, Ki67 was down-regulated, thyroid transcription factor 1 (TTF-1) and Caspase 3 were up-regulated in TRIM7 overexpression group in xenograft model. It is very impressive that TRIM7t (a truncated TRIM7 without C-terminal sequence that different with GNIP1) had little effect on the tumor growth in vivo. These findings highlight a curious mechanism for negative regulation of NF-kappa B signaling pathway by TRIM7 and demonstrate that TRIM7 would be a potential therapeutic target for lung cancer.

4.
Int J Biol Macromol ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31756473

RESUMO

A novel sustained-release matrix tablet was developed through wet granulation by using oxidized konjac glucomannan-cassava starch (OKGM-CS) and sucrose esters (SE) as excipients. OKGM-CS treated by dry heat exhibited low solubility and swelling power, indicating that it might be a potential adjuvant for sustained-release drug formulations. SE incorporation significantly decreased the porosity and swelling rates of tablets and retarded drug release. Tablets containing SE with an HLB value of 5 displayed better sustained-release performance, the cumulative release decreased from 94.36% to 83.29% and MDT increased from 4.50 h to 5.79 h. All these findings suggest the potential of OKGM-CS and SE as novel sustained-release agents for matrix tablets.

5.
Pathol Res Pract ; 215(10): 152592, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474315

RESUMO

Breast cancer is the most common malignant tumor among women in China, which seriously threatens women's physical and mental health. Tumorigenesis is closely related to the dysregulation of cell cycle. The cell cycle progression includes interphase and mitotic phase (M phase). Cyclin B1 is a key protein in regulating M phase, which is essential for the whole cell cycle progression. CyclinB1 can be degraded through ubiquitination mediated by the anaphase promoting complex/cyclosome (APC/C). However, the mechanism of how CyclinB1 is deubiquitinated in breast cancer still remains unclear. In this study, we discovered that CyclinB1 interacted with ubiquitin-specific peptidase 14 (USP14). Based on the deubiquitinating function of USP14, we detected the effect of USP14 on the ubiquitination of CyclinB1. Inhibiting the activity of USP14 or USP14 knockdown significantly increased the ubiquitination of CyclinB1. In accordance with this, knocking down USP14 arrested cell cycle at G2/M phase. Knocking down USP14 with siRNAs significantly inhibited the proliferation and migration of breast cancer cells. In conclusion, our study demonstrated that USP14 regulated the cell cycle of breast cancer cells by regulating the ubiquitination of CyclinB1, which will provide a solid theoretical basis for the development of anti-cancer drugs targeting USP14.


Assuntos
Neoplasias da Mama/metabolismo , Ciclo Celular/fisiologia , Ciclina B1/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Ciclina B1/genética , Feminino , Humanos , Ubiquitina Tiolesterase/genética
6.
Cell Cycle ; 18(9): 1019-1032, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31023143

RESUMO

The anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase, is responsible for the transition from metaphase to anaphase and the exit from mitosis. The anaphase promoting complex subunit 10 (APC10), a subunit of the APC/C, executes a vital function in substrate recognition. However, no research has reported the connection between APC10 and cancer until now. In this study, we uncovered a novel, unprecedented role of APC10 in tumor progression, which is independent of APC/C. First, aberrant increase of APC10 expression was validated in non-small cell lung cancer (NSCLC) cells and tissues, and the absence of APC10 repressed cell proliferation and migration. Of great interest, we found that APC10 inhibition induced cell cycle arrest at the G0/G1 phase and reduced the expression of the APC/C substrate, Cyclin B1; this finding is different from the conventional concept of the accumulation of Cyclin B1 and cell cycle arrest in metaphase. Further, APC10 was found to interact with glutaminase C (GAC), and the inhibition of APC10 weakened glutamine metabolism and induced excessive autophagy. Taken together, these findings identify a novel function of APC10 in the regulation of NSCLC tumorigenesis and point to the possibility of APC10 as a new target for cancer therapy.

7.
Biochem Cell Biol ; 97(4): 397-405, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30475643

RESUMO

Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon, exhibits broad-spectrum antitumor activity via different molecular mechanisms. In this study, we investigated the effect of shikonin on mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanisms underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK and PGC1α pathways), which aggravated the oxidative stress and nutrient deficiency. Our results indicate a novel role of shikonin in triggering mitochondria dysfunction via the PKM2-AMPK-PGC1α signaling pathway and provide a promising therapeutic approach for the treatment of HCC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos Fitogênicos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Estrutura Molecular , Naftoquinonas/química , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/antagonistas & inibidores , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Relação Estrutura-Atividade , Hormônios Tireóideos/metabolismo
8.
Mol Cell Endocrinol ; 461: 155-164, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-28893569

RESUMO

Fatty acid binding protein 4 (FABP4) is a member of the fatty acid binding protein family which involved in a variety of biological cellular processes, including tumorigenesis. However, the role of this key adipokine in cervical cancer is still unclear. In this study, we explored the function of FABP4 in cervical cancer and the underlying molecular mechanisms. FABP4 was specifically elevated in tissue samples from patients with cervical squamous cell carcinoma (CSCC) but not with cervical adenocarcinoma, and the level of FABP4 was correlated with E-cadherin and Vimentin expression. In vitro, exogenous FABP4 promoted the migration and invasion of CSCC cells in a dose-dependent manner, and reorganized the actin cytoskeletons in F-Actin staining and TGF-ß induced EMT assays. Importantly, the AKT/GSK3ß/Snail pathway appears to be involved in FABP4-induced EMT in CSCC cells. In conclusion, our research demonstrated elevated FABP4 promoted EMT via the activation of AKT/GSK3ß/Snail pathway in CSCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Transição Epitelial-Mesenquimal , Proteínas de Ligação a Ácido Graxo/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Citoesqueleto de Actina/metabolismo , Adulto , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Vimentina/metabolismo
9.
Am J Transl Res ; 9(9): 4217-4226, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979695

RESUMO

The transcription factor, Grainyhead-like 2 (GRHL2), is involved in wound healing, epidermal integrity, and epithelial-to-mesenchymal transition (EMT) in various biological processes; however, the biological function of GRHL2 in non-small cell lung cancer (NSCLC) is unknown. In the current study, we investigated the effect of GRHL2 on cell growth and migration in NSCLC cell lines and clinical tissues. Immunohistochemical analysis of clinical NSCLC specimens revealed that patients with high GRHL2 expression were associated with poor prognosis compared to patients with low GRHL2 expression. GRHL2 overexpression promoted cell growth and colony formation, and simultaneously suppressed cell migration in NSCLC cells. Furthermore, GRHL2 decreased the transcriptional activity of RhoG by directly binding to the RhoG promoter region. These findings confirm that GRHL2 plays an important role in regulating cell proliferation and migration in NSCLC.

10.
Life Sci ; 183: 110-115, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28684065

RESUMO

Cancer cells are well documented to reprogram their metabolism in order to support the maintenance and reproduction. 3-oxoacid CoA-transferase 1 (OXCT1) is a key enzyme in ketone body metabolism that catalyzes the first and rate-determining step of ketolysis. The product of OXCT1 converts to acetyl-CoA and finally fed into the tricarboxylic acid cycle for oxidation and ATP production. However, little is known of its regulation right now. Recently, some studies suggested that OXCT1 participates in tumorigenesis and signaling in cancer cells. Furthermore, our recent work showed that a marked elevation of OXCT1 expression in different categories of cancer cells. Here we review the metabolic functions of OXCT1 and its surprising roles in supporting the biological hallmarks of malignancy. We also review recent efforts in exploring the mechanism responsible for the tumor promoting effect of OXCT1 and suggest a novel therapeutic target for cancer therapy.


Assuntos
Coenzima A-Transferases/metabolismo , Cetonas/metabolismo , Neoplasias/metabolismo , Acetilcoenzima A/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Coenzima A-Transferases/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , Transdução de Sinais
11.
Int J Biol Macromol ; 101: 9-15, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28283453

RESUMO

Starches were isolated from South China 5 (SC5) cassava harvested for 7, 8, 9, 10 and 11 months. During growth, the granule size, lamellar structure, crystalline structure and digestibility changed slightly, while the amylose content varied between 20.93% and 22.61%. However, the molecular weight showed an obvious increase as the harvesting time increased to 9 months, and then decreased during 9-11 months. The pasting behaviors were greatly affected by harvesting time. A shorter growth time led to higher pasting temperature, and lower peak, breakdown and setback viscosities. This trend became contrary when the growth time prolonged from 9 to 11 months. Hence, the starch harvested at 9 months showed the lowest pasting temperature (64.6°C), but highest paste viscosity (2105cP) and retrogradation tendency. All these results confirm that the growth time of 9 months was the turning point for the physicochemical features of SC5 during growth. This study provides fundamental data for rationally tailoring cassava starch properties by simply controlling the harvest time.


Assuntos
Fenômenos Químicos , Manihot/química , Amido/química , Amilose/análise , Temperatura Alta , Peso Molecular , Amido/metabolismo , Viscosidade
12.
Oncotarget ; 8(17): 28063-28073, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28039459

RESUMO

Metabolic reprogramming is critical for cancer cell proliferation. Glutaminolysis which provides cancer cells with bioenergetics and intermediates for macromolecular synthesis have been intensively studied in recent years. Glutaminase C (GAC) is the first and rate-limiting enzyme in glutaminolysis and plays important roles in cancer initiation and progression. We previously screened a small molecule named 968, a specific inhibitor of GAC, to block the proliferation of human breast cancer cells. In this study, we found that 968 effectively inhibited NSCLC cell proliferation and migration and arrested G0/G1 phase of cell cycle. Furthermore, we demonstrated that 968 inhibited the EGFR/ERK pathway via decreasing the expression of EGFR and phospho-ERK. Apart from this, we discovered that 968 treatment induced autophagy to protect cells against apoptosis and the combination of 968 with autophagy inhibitor Chloroquine (CQ) had synergistic effects on the growth of NSCLC cells. Thus, our study pointed out a new therapeutic strategy for NSCLC treatment by combination of 968 with CQ.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Inibidores Enzimáticos/farmacologia , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glutaminase/antagonistas & inibidores , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos
13.
Cell Signal ; 30: 59-66, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27871936

RESUMO

COMMD protein family is an evolutionarily conserved gene family implicated in a number of critical processes including inflammation, copper homeostasis, sodium balance, endosomal sorting and cancer. In an effort to profile the expression pattern of COMMD family in several non-small cell lung cancer (NSCLC) cell lines, we found that compared with that in human bronchial epithelial (HBE) cells, the mRNA expression levels of five COMMD genes including COMMD3, COMMD4, COMMD5, COMMD6 and COMMD8 were significantly down-regulated, whereas COMMD9 was up-regulated in NSCLC cell lines. Here we reported that the expression of COMMD9 protein was significantly increased in various NSCLC cell lines and tissue samples. SiRNA-induced knocking down of COMMD9 inhibited proliferation and migration, arrested cell cycle at G1/S transition and induced autophagy in NSCLC cells. Mechanistically, COMMD9 interacted with the TFDP1 through COMM domain, and DNA-binding domain of TFDP1 was required for this interaction. Moreover, decreased expression COMMD9 attenuated TFDP1/E2F1 activation accompanied with enhanced p53 signaling pathway. Taken together, these findings demonstrate that COMMD9 participates in TFDP1/E2F1 activation and plays a critical role in non-small cell lung cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Fator de Transcrição E2F1/genética , Neoplasias Pulmonares/genética , Fator de Transcrição DP1/genética , Transcrição Genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Autofagia/genética , Adesão Celular/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Fase G1/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Ligação Proteica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fase S/genética , Transdução de Sinais/genética , Ensaio Tumoral de Célula-Tronco , Proteína Supressora de Tumor p53/metabolismo
14.
Life Sci ; 157: 131-139, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27265384

RESUMO

AIMS: Dihydromyricetin (DMY), a flavonoid component isolated from Ampelopsis grossedentata, was recently reported to ameliorate nonalcoholic fatty liver disease (NAFLD) in patients. However, the underlying mechanisms of this action remain unknown. Here, we evaluate the effect of DMY on an in vitro model of NAFLD and investigate the signal transduction pathways underlying DMY treatment. MAIN METHODS: Oleic acid (OA) induced hepatic steatosis was established in L02 and HepG2 cells as in vitro model of NAFLD. Cell apoptosis, lipid accumulation and oxide stress were evaluated by flow cytometry, oil red O staining, and cellular biochemical assays, respectively. Signaling pathways involved in lipid metabolism including PPARγ, AMPK, and AKT were investigated by Western blot and RT-qPCR. KEY FINDINGS: DMY protected cells against apoptosis and lipid accumulation induced by oleic acid. DMY decreased the levels of cellular triglycerides (TG), cholesterol (TC) and malondialdehyde (MDA), while at the same time increasing the level of superoxide dismutase (SOD). DMY suppressed the expression of PPARγ and the phosphorylation of AKT, and promoted the phosphorylation of AMPK. SIGNIFICANCE: Our study suggests that DMY ameliorates OA-induced hepatic steatosis by inhibiting cell apoptosis, lipid accumulation and oxide stress. Furthermore, the effect of DMY is likely associated with its role in the regulating of PPARγ, AMPK and AKT signaling pathways.


Assuntos
Flavonóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Ácido Oleico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Células Hep G2 , Humanos
15.
Oncotarget ; 7(1): 610-21, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26575584

RESUMO

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has been approved based on the clinical benefit in non-small cell lung cancer (NSCLC) patients over the past decade. Unfortunately, cancer cells become resistant to this agent via various mechanisms, and this limits the improvement in patient outcomes. Thus, it is urgent to develop novel agents to overcome erlotinib resistance. Here, we propose a novel strategy to overcome acquired erlotinib resistance in NSCLC by inhibiting glutaminase activity. Compound 968, an inhibitor of the glutaminase C (GAC), when combined with erlotinib potently inhibited the cell proliferation of erlotinib-resistant NSCLC cells HCC827ER and NCI-H1975. The combination of compound 968 and erlotinib not only decreased GAC and EGFR protein expression but also inhibited GAC activity in HCC827ER cells. The growth of erlotinib-resistant cells was glutamine-dependent as proved by GAC gene knocked down and rescue experiment. More importantly, compound 968 combined with erlotinib down-regulated the glutamine and glycolysis metabolism in erlotinib-resistant cells. Taken together, our study provides a valuable approach to overcome acquired erlotinib resistance by blocking glutamine metabolism and suggests that combination of EGFR-TKI and GAC inhibitor maybe a potential treatment strategy for acquired erlotinib-resistant NSCLC.


Assuntos
Benzofenantridinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Glutaminase/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Apoptose/genética , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Relação Dose-Resposta a Droga , Citometria de Fluxo , Glutaminase/genética , Glutaminase/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mitocôndrias/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Fatores de Tempo
16.
PLoS One ; 10(11): e0142596, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26599082

RESUMO

TRIM protein family is an evolutionarily conserved gene family implicated in a number of critical processes including inflammation, immunity, antiviral and cancer. In an effort to profile the expression patterns of TRIM superfamily in several non-small cell lung cancer (NSCLC) cell lines, we found that the expression of 10 TRIM genes including TRIM3, TRIM7, TRIM14, TRIM16, TRIM21, TRIM22, TRIM29, TRIM59, TRIM66 and TRIM70 was significantly upregulated in NSCLC cell lines compared with the normal human bronchial epithelial (HBE) cell line, whereas the expression of 7 other TRIM genes including TRIM4, TRIM9, TRIM36, TRIM46, TRIM54, TRIM67 and TRIM76 was significantly down-regulated in NSCLC cell lines compared with that in HBE cells. As TRIM59 has been reported to act as a proto-oncogene that affects both Ras and RB signal pathways in prostate cancer models, we here focused on the role of TRIM59 in the regulation of NSCLC cell proliferation and migration. We reported that TRIM59 protein was significantly increased in various NSCLC cell lines. SiRNA-induced knocking down of TRIM59 significantly inhibited the proliferation and migration of NSCLC cell lines by arresting cell cycle in G2 phase. Moreover, TRIM59 knocking down affected the expression of a number of cell cycle proteins including CDC25C and CDK1. Finally, we knocked down TRIM59 and found that p53 protein expression levels did not upregulate, so we proposed that TRIM59 may promote NSCLC cell growth through other pathways but not the p53 signaling pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Ciclo Celular/genética , Proteínas de Membrana/genética , Metaloproteínas/genética , Proteína Supressora de Tumor p53/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/biossíntese , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Proteínas de Membrana/biossíntese , Metaloproteínas/biossíntese , RNA Interferente Pequeno , Transdução de Sinais/genética , Ativação Transcricional/genética , Proteína Supressora de Tumor p53/genética
17.
J Pharmacol Sci ; 128(3): 116-24, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26220468

RESUMO

Honokiol (HK), a biphenolic neolignan isolated from Magnolia officinalis, has been reported to possess anti-inflammatory and anti-angiogenic activaties. In this study, our aim was to investigate anti-psoriatic activities of HK and the involved mechanisms. In vitro, the effects of HK on the regulation of Th1/Th2 and TNF-α-induced NF-κB (p65) activation were analyzed by respective FCS and immunofluorescence. Additionally, the K14-VEGF transgenic model was used for the in vivo study. ELISA and Q-PCR were performed to evaluate serum levels of Th1/Th2 cytokines and their corresponding mRNA expressions. Effects on VEGFR-2 and p65 activation, as well as other angiogenic and inflammatory parameters were studied by immunostainings. Importantly, we found that HK significantly decreased the ratio of Th1/Th2-expression CD4(+) T cells and inhibited TNF-α-induced activation of NF-κB. The morphology and histological features of psoriasis were effectively improved by HK treatment. The expression of TNF-α and IFN-γ, and their corresponding mRNA levels were down-regulated and the expression of nuclear p65, VEGFR-2, as well as related phosphorylated proteins (p-VEGFR-2, p-ERK1/2, p-AKT and p-p38) were also suppressed. Overall, these results in our study suggested that HK exhibits anti-psoriatic effects through the inhibition of NF-κB and VEGFR-2.


Assuntos
Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Lignanas/farmacologia , Lignanas/uso terapêutico , Terapia de Alvo Molecular , NF-kappa B/antagonistas & inibidores , Fitoterapia , Psoríase/tratamento farmacológico , Psoríase/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese , Animais , Anti-Inflamatórios , Compostos de Bifenilo/isolamento & purificação , Linfócitos T CD4-Positivos , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Lignanas/isolamento & purificação , Magnolia , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Psoríase/patologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Biochem Biophys Res Commun ; 462(4): 288-93, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25935488

RESUMO

TNF-α is a dominant inflammatory mediator in the pathogenesis of inflammatory diseases including rheumatoid arthritis. In our research, we discovered 2-chloro-N-(4-(2-morpholinoethoxy)phenyl)quinazolin-4-amine (9c) exhibited an outstanding anti-inflammatory activity on inhibiting TNF-α production with an IC50 of 8.86 µM in RAW264.7 cells. Interestingly, 9c had no effect on mRNA level of TNF-α but up-regulated the precursor of TNF-α (pro-TNF-α). Then, we studied TNF-α converting enzyme (TACE), which is the most important proteases responsible for the release of TNF-α from pro-TNF-α to soluble TNF-α. The results showed 9c reduced TACE both on the levels of mRNA and protein in a dose-dependent manner. In vivo study, collagen-induced arthritis (CIA) mice were treated by 9c orally. 9c exhibited significant anti-arthritis effect by ameliorating arthritic score, reducing inflammatory cell infiltration, protecting joints from destruction and decreasing the production of systemic TNF-α, IL-6, IL-1ß. The underlying mechanism of 9c on CIA was coincided with the in vitro, which was mediated by TACE. In conclusion, we discovered a novel quinazoline derivative which ameliorates arthritis through inhibiting production of TNF-α mediated by TACE for the first time.


Assuntos
Proteínas ADAM/metabolismo , Artrite Experimental/tratamento farmacológico , Colágeno/administração & dosagem , Quinazolinas/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteína ADAM17 , Animais , Linhagem Celular , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Camundongos Endogâmicos DBA , Quinazolinas/farmacologia , RNA Mensageiro/genética , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
19.
Mol Divers ; 19(2): 333-46, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25672287

RESUMO

Diabetes mellitus, commonly characterized by hyperglycemia, is a group of metabolic diseases. Some oral anti-diabetic drugs show poor tolerability during chronic treatment, and associate with undesired side effects. Recent advances in the understanding of physiological functions of incretins and their degrading enzyme dipeptidyl peptidase DPP-IV have led to the discovery of DPP-IV inhibitors as a new class of oral anti-diabetic drugs. Several DPP-IV inhibitors have different chemical structures of which the xanthine scaffold has specific advantages. Combining previous work with the research strategy of pharmacophore hybridization, we retained this scaffold and synthesized a new series of amino-alcohol or diamino-modified xanthine compounds. Some xanthines exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound 40 [Formula: see text] exhibits a good in vivo efficacy in reducing glucose excursion at a single dose and a better chronic effect in reducing body weight than metformin in DIO mice. In other words, the combined effect improved the pathological state of DIO mice.


Assuntos
Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Desenho de Fármacos , Glucose/metabolismo , Homeostase , Xantina/química , Animais , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Homeostase/efeitos dos fármacos , Camundongos , Fatores de Tempo , Xantina/farmacologia
20.
Sci Rep ; 5: 7697, 2015 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-25571970

RESUMO

To overcome drug resistance caused by apoptosis deficiency in patients with non-small cell lung carcinoma (NSCLC), there is a need to identify other means of triggering apoptosis-independent cancer cell death. We are the first to report that isogambogenic acid (iso-GNA) can induce apoptosis-independent autophagic cell death in human NSCLC cells. Several features of the iso-GNA-treated NSCLC cells indicated that iso-GNA induced autophagic cell death. First, there was no evidence of apoptosis or cleaved caspase 3 accumulation and activation. Second, iso-GNA treatment induced the formation of autophagic vacuoles, increased LC3 conversion, caused the appearance of autophagosomes and increased the expression of autophagy-related proteins. These findings provide evidence that iso-GNA induces autophagy in NSCLC cells. Third, iso-GNA-induced cell death was inhibited by autophagic inhibitors or by selective ablation of Atg7 and Beclin 1 genes. Furthermore, the mTOR inhibitor rapamycin increased iso-GNA-induced cell death by enhancing autophagy. Finally, a xenograft model provided additional evidence that iso-GNA exhibited anticancer effect through inducing autophagy-dependent cell death in NSCLC cells. Taken together, our results demonstrated that iso-GNA exhibited an anticancer effect by inducing autophagy-dependent cell death in NSCLC cells, which may be an effective chemotherapeutic agent that can be used against NSCLC in a clinical setting.


Assuntos
Antineoplásicos/toxicidade , Autofagia/efeitos dos fármacos , Xantonas/toxicidade , Apoptose , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 7 Relacionada à Autofagia , Proteína Beclina-1 , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/toxicidade , Serina-Treonina Quinases TOR/metabolismo , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Xantonas/química
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