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1.
Oncotarget ; 7(36): 58470-58482, 2016 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-27542262

RESUMO

Eukaryotic elongation factor 2 (EF2), is a critical enzyme solely responsible for catalyzing the translocation of the elongated peptidyl-tRNA from the A to P sites of the ribosome during the process of protein synthesis. EF2 is found to be highly expressed in a variety of malignant tumors and is correlated with cancer cell progression and recurrence. The present study was designed to uncover the function of EF2 on lung squamous cell carcinoma (LSCC) cancer cell growth and progression. Our results from clinical tissue studies showed that EF2 protein was significantly overexpressed in LSCC tissues, compared with the adjacent normal lung tissues, which was confirmed by western blotting and tissue microarray. Forced expression of EF2 resulted in the enhancement of lung squamous carcinoma NCI-H520 cells growth through promotion of G2/M progression in cell cycle, activating Akt and Cdc2/Cyclin B1. In nude mice cancer xenograft model, overexpression of EF2 significantly facilitated cell proliferation in vivo. Furthermore, forced expression of EF2 in the cells increased the capabilities of migration and invasion by changing the expressions of EMT-related proteins and genes. These results provided novel insights into the role of EF2 in tumorigenesis and progression in LSCC. EF2-targeted therapy could become a good strategy for the clinical treatment of LSCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/genética , Transplante de Neoplasias , Proteômica/métodos , Análise Serial de Tecidos
2.
Mol Cancer Ther ; 13(8): 1991-2003, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24899685

RESUMO

Chemoresistance is a major cause of cancer treatment failure. Tumor-initiating cells (TIC) have attracted a considerable amount of attention due to their role in chemoresistance and tumor recurrence. Here, we evaluated the small molecule Aurora kinase inhibitor AKI603 as a novel agent against TICs in breast cancer. AKI603 significantly inhibited Aurora-A (AurA) kinase and induced cell-cycle arrest. In addition, the intragastric administration of AKI603 reduced xenograft tumor growth. Interestingly, we found that breast cancer cells that were resistant to epirubicin expressed a high level of activated AurA and also have a high CD24(Low)/CD44(High) TIC population. The inhibition of AurA kinase by AKI603 abolished the epirubicin-induced enrichment of TICs. Moreover, AKI603 suppressed the capacity of cells to form mammosphere and also suppressed the expression of self-renewal genes (ß-catenin, c-Myc, Sox2, and Oct4). Thus, our work suggests the potential clinical use of the small molecule Aurora kinase inhibitor AKI603 to overcome drug resistance induced by conventional chemotherapeutics in breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Animais , Aurora Quinase A/antagonistas & inibidores , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Sinergismo Farmacológico , Epirubicina/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Esferoides Celulares/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Chin Med J (Engl) ; 124(20): 3341-6, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22088532

RESUMO

BACKGROUND: Glucose regulated protein 78 (GRP78), an endoplasmic reticulum (ER) chaperone, plays a critical role in chemotherapy resistance in a variety of cancers. In this study, we investigated the up-regulation of GRP78 induced by A23187 and its association with the chemotherapeutical sensibility to cisplatin in human lung cancer cell line SPCA1. METHODS: SPCA1 cells were pretreated with A23187 at different concentrations. The expression of GRP78 at the mRNA level was analyzed by RT-PCR; the expression of GRP78 at the protein level was determined by Western blotting and immunofluorescence assay. Cell survival was determined by MTT assay. Cell apoptosis was analyzed by flow cytometry. RESULTS: The expression of GRP78 at both the mRNA and protein levels was obviously induced by A23187 in SPCA1 cells, with an elevation of GRP78 by 2.1-fold at the mRNA level and by 3.8-fold at the protein level compared to the control. There was a dose-dependent response. Survival curve analysis demonstrated that A23187 induction caused a significant reduction of survival for the cells subjected to cisplatin treatment (P < 0.05). After treatment by cisplatin, the percentage of apoptotic cells in the A23187 pretreated group increased about three fold compared with the control group ((27.53 ± 4.32)% vs. (9.25 ± 3.64)%, P < 0.05). CONCLUSIONS: A23187 treatment was fairly effective for the induction of GRP78 in SPCA1 cells at both the mRNA and protein levels. To a certain extent, GRP78 up-regulation by A23187 was associated with the enhancement of drug sensitivity to cisplatin in human lung cancer cell line SPCA1.


Assuntos
Antineoplásicos/farmacologia , Calcimicina/farmacologia , Cisplatino/farmacologia , Proteínas de Choque Térmico/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Citometria de Fluxo , Proteínas de Choque Térmico/genética , Humanos , Neoplasias Pulmonares/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Zhonghua Zhong Liu Za Zhi ; 32(10): 748-51, 2010 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-21163064

RESUMO

OBJECTIVE: China has the highest incidence and mortality of esophageal carcinoma in the world, and the esophageal squamous cell carcinoma (ESCC) is the major type. In this study, the authors investigated the expression of Aurora-A in stage T3 esophageal squamous cell carcinomas (ESCC) with positive and negative lymph node metastasis, and analyzed its relationship with prognosis of ESCC patients. METHODS: ESCC tissue arrays including 212 specimens had been constructed. The expression of Aurora-A in both ESCC tissues and adjacent normal tissues was determined by immunohistochemical staining. The correlation between Aurora-A protein levels and lymph node status in ESCC and survival rate were statistically analyzed. RESULTS: The positive expression of Aurora-A was 74.07% (140/189) in tumor tissues and 18.52% (35/189) in adjacent normal tissues, showing a significant difference between them (χ(2) = 105.162, P < 0.05). In tumors with positive lymph nodes, strong positive expression of Aurora-A was found in 42.99% (46/107), while only 7.37% (7/95) in tumors with negative lymph nodes, with a statistically significant difference (χ(2) = 36.132, P < 0.05). The cumulative survival rate of the patients with strong Aurora-A-positive tumors was significantly lower than that in patients with Aurora-A-negative tumors (P = 0.0042, P < 0.05). CONCLUSION: The positive expression of Aurora-A in ESCC tissues is much higher than that in adjacent normal tissues. The expression of Aurora-A is higher in lymph node-positive tumors than in the lymph node-negative ones. There is a significantly longer cumulative survival rate in patients with negative Aurora-A expression than that in patients with strong positive Aurora-A expression.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aurora Quinases , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida
5.
Ai Zheng ; 24(7): 792-5, 2005 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-16004802

RESUMO

BACKGROUND & OBJECTIVE: Recent researches found that Aurora-A overexpresses in various malignancies. This study was to detect the expression of Aurora-A in lung cancer cell lines PG (highly-metastatic giant cell lung cancer), A549 (lung adenocarcinoma), and NCI-H460 (large cell lung cancer) and explore its correlation to DNA content, provide a theoretical basis for screening tumor marker and molecular therapeutic target of lung cancer. METHODS: mRNA and protein levels of Aurora-A in PG, A549, and NCI-H460 cells were detected by reverse transcription-polymerase chain reaction(RT-PCR) and Western blot. Flow cytometry was used to analyze DNA contents in cell cycles of PG, A549, and NCI-H460 cells. RESULTS: mRNA level of Aurora-A was 1.14 in PG cells, 1.16 in A549 cells, and 0.84 in NCI-H460 cells, respectively; protein level of Aurora-A was 8.96 in PG cells, 21.13 in A549 cells, and 6.43 in NCI-H460 cells, respectively. The proportion of cells with tetraploid DNA was 19.88% in PG cells, 14.97% in A549 cells, and 10.6% in NCI-H460 cells, respectively (P<0.01); the proportion of cells with polyploid DNA was 2.66% in PG cells, 3.59% in A549 cells, and 2.30% in NCI-H460 cells, respectively. CONCLUSION: Aurora-A is overexpressed in the 3 lung cancer cell lines, but the mRNA levels are different.


Assuntos
Adenocarcinoma/metabolismo , Carcinoma de Células Gigantes/metabolismo , Carcinoma de Células Grandes/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Serina-Treonina Quinases/biossíntese , Adenocarcinoma/genética , Aurora Quinases , Carcinoma de Células Gigantes/genética , Carcinoma de Células Grandes/genética , Linhagem Celular Tumoral , DNA de Neoplasias/genética , Humanos , Neoplasias Pulmonares/genética , Poliploidia , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
J Chromatogr B Analyt Technol Biomed Life Sci ; 816(1-2): 145-51, 2005 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-15664344

RESUMO

The p16 tumor suppressor gene is inactivated by promoter region hypermethylation in many types of tumor. Recent studies showed that aberrant methylation of the p16 gene is an early event in many tumors, especially in lung cancer, and may constitute a new biomarker for early detection and monitoring of prevention trials. We detected tumor-associated aberrant hypermethylation of the p16 gene in plasma and tissue DNA from 153 specimens using a modified semi-nested methylation-specific PCR (MSP) combining plastic microchip electrophoresis or slab gel electrophoresis, respectively. Specimens were from 79 lung cancer patients, 15 abdominal tumor patients, 30 positive controls and 30 negative controls. The results showed that the positive rate obtained by microchip electrophoresis was more than 26.6% higher and the same specificity was kept when compared with slab gel electrophoresis. The microchip electrophoresis can rapidly and accurately analyze the PCR products of methylated DNA and obviously improve the positive rate of diagnosis of cancer patients when compared with gel electrophoresis. This method with the high assay sensitivity might be used for detection of methylation of p16 gene and even to facilitate early diagnosis of cancer patients.


Assuntos
Metilação de DNA , Eletroforese em Microchip/métodos , Genes p16 , Neoplasias/genética , Neoplasias Abdominais/sangue , Neoplasias Abdominais/genética , Eletroforese em Microchip/instrumentação , Estudos de Viabilidade , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Polimetil Metacrilato , Sensibilidade e Especificidade
7.
Ai Zheng ; 23(1): 99-103, 2004 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-14720385

RESUMO

In recent twenty years, the incidence of lung cancer has increased quickly in our country. Till now, the morbidity and mortality of lung cancer have occupied the top of the cancers. Early diagnosis is the most important key to increase the five-year survival rate. This review is attempted to summarize the early hereditary events during the development of lung cancer, mainly including the mutation of p53 gene, the abnormal methylation of the promoter area of p16 gene, the loss of heterozygosity of 3p, 8p, 9p, 5q, etc. The purpose is to seek the biological markers during the development of lung cancer to provide theoretical basis for treatment of lung cancer.


Assuntos
Neoplasias Pulmonares/genética , Lesões Pré-Cancerosas/genética , Genes myc , Genes p53 , Genes ras , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/patologia , Lesões Pré-Cancerosas/patologia
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