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[PMID]: | 28993193 |
[Au] Autor: | Yang L; Wen Y; Lv G; Lin Y; Tang J; Lu J; Zhang M; Liu W; Sun X |
[Ad] Endereço: | Shenzhen Tumor Immuno-gene Therapy Clinical Application Engineering Lab, Biobank of Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, PR China; Institute of Immunology of Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510060, G |
[Ti] Título: | α-Lipoic acid inhibits human lung cancer cell proliferation through Grb2-mediated EGFR downregulation. |
[So] Source: | Biochem Biophys Res Commun;494(1-2):325-331, 2017 Dec 09. | [Is] ISSN: | 1090-2104 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | BACKGROUND: Alpha lipoic acid (α -LA) is a naturally occurring antioxidant and metabolic enzyme co-factor. Recently, α -LA has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α -LA on non-small cell lung cancer (NSCLC) development remain unclear. METHODS: The CCK-8 assay was used to assess cell proliferation in NSCLC cell lines after α -LA treatment. The expression of growth factor receptor-bound protein 2 (Grb2), cyclin-dependent kinase (CDK)-2, CDK4, CDK6, Cyclin D3, Cyclin E1, Ras, c-Raf, epidermal growth factor receptor (EGFR), ERK1/2 and activated EGFR and ERK1/2 was evaluated by western blotting. Grb2 levels were restored in α-LA-treated cells by transfection of a plasmid carrying Grb2 and were reduced in NSCLC cells via specific siRNA-mediated knockdown. RESULTS: α -LA dramatically decreased NSCLC cell proliferation by downregulating Grb2; in contrast, Grb2 overexpression significantly prevented α-LA-induced decrease in cell growth in vitro. Western blot analysis indicated that α-LA decreased the levels of phospho-EGFR, CDK2/4/6, Cyclins D3 and E1, which are associated with the inhibition of G1/S-phase transition. Additional experiments indicated that Grb2 inhibition partially abolished EGF-induced phospho-EGFR and phospho-ERK1/2 activity. In addition, α-LA exerted greater inhibitory effects than gefitinib on NSCLC cells by preventing EGF-induced EGFR activation. CONCLUSION: For the first time, these findings provide the first evidence that α-LA inhibits cell proliferation through Grb2 by suppressing EGFR phosphorylation and that MAPK/ERK is involved in this pathway. |
[Mh] Termos MeSH primário: |
Antineoplásicos/farmacologia Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos Proteína Adaptadora GRB2/antagonistas & inibidores Regulação Neoplásica da Expressão Gênica Ácido Tióctico/farmacologia
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[Mh] Termos MeSH secundário: |
Células A549 Proliferação Celular/efeitos dos fármacos Ciclina D3/genética Ciclina D3/metabolismo Ciclina E/genética Ciclina E/metabolismo Quinase 2 Dependente de Ciclina/genética Quinase 2 Dependente de Ciclina/metabolismo Quinase 4 Dependente de Ciclina/genética Quinase 4 Dependente de Ciclina/metabolismo Quinase 6 Dependente de Ciclina/genética Quinase 6 Dependente de Ciclina/metabolismo Proteína Adaptadora GRB2/genética Proteína Adaptadora GRB2/metabolismo Seres Humanos Proteína Quinase 1 Ativada por Mitógeno/genética Proteína Quinase 1 Ativada por Mitógeno/metabolismo Proteína Quinase 3 Ativada por Mitógeno/genética Proteína Quinase 3 Ativada por Mitógeno/metabolismo Proteínas Oncogênicas/genética Proteínas Oncogênicas/metabolismo Fosforilação/efeitos dos fármacos Proteínas Proto-Oncogênicas c-raf/genética Proteínas Proto-Oncogênicas c-raf/metabolismo RNA Interferente Pequeno/genética RNA Interferente Pequeno/metabolismo Receptor do Fator de Crescimento Epidérmico/genética Receptor do Fator de Crescimento Epidérmico/metabolismo Transdução de Sinais Proteínas ras/genética Proteínas ras/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Antineoplastic Agents); 0 (CCND3 protein, human); 0 (CCNE1 protein, human); 0 (Cyclin D3); 0 (Cyclin E); 0 (GRB2 Adaptor Protein); 0 (GRB2 protein, human); 0 (Oncogene Proteins); 0 (RNA, Small Interfering); 73Y7P0K73Y (Thioctic Acid); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.1 (Proto-Oncogene Proteins c-raf); EC 2.7.11.22 (CDK2 protein, human); EC 2.7.11.22 (CDK4 protein, human); EC 2.7.11.22 (CDK6 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 2); EC 2.7.11.22 (Cyclin-Dependent Kinase 4); EC 2.7.11.22 (Cyclin-Dependent Kinase 6); EC 2.7.11.24 (MAPK1 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3); EC 3.6.5.2 (ras Proteins) |
[Em] Mês de entrada: | 1711 |
[Cu] Atualização por classe: | 171108 |
[Lr] Data última revisão:
| 171108 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 171011 |
[St] Status: | MEDLINE |
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