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1.
Int J Mol Sci ; 23(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36077593

RESUMO

Overexpression of human epidermal growth factor receptor-2 (HER-2) occurs in 20% of all breast cancer subtypes, especially those that present the worst prognostic outcome through a very invasive and aggressive tumour. HCC-1954 (HER-2+) is a highly invasive, metastatic cell line, whereas MCF-7 is mildly aggressive and non-invasive. We investigated membrane proteins from both cell lines that could have a pivotal biological significance in metastasis. Membrane protein enrichment for HCC-1954 and MCF-7 proteomic analysis was performed. The samples were analysed and quantified by mass spectrometry. High abundance membrane proteins were confirmed by Western blot, immunofluorescence, and flow cytometry. Protein interaction prediction and correlations with the Cancer Genome Atlas (TCGA) patient data were conducted by bioinformatic analysis. In addition, ß1 integrin expression was analysed by Western blot in cells upon trastuzumab treatment. The comparison between HCC-1954 and MCF-7 membrane-enriched proteins revealed that proteins involved in cytoskeleton organisation, such as HER-2, αv and ß1 integrins, E-cadherin, and CD166 were more abundant in HCC-1954. ß1 integrin membrane expression was higher in the HCC-1954 cell line resistant after trastuzumab treatment. TCGA data analysis showed a trend toward a positive correlation between HER-2 and ß1 integrin in HER-2+ breast cancer patients. Differences in protein profile and abundance reflected distinctive capabilities for aggressiveness and invasiveness between HCC-1954 and MCF-7 cell line phenotypes. The higher membrane ß1 integrin expression after trastuzumab treatment in the HCC-1954 cell line emphasised the need for investigating the contribution of ß1 integrin modulation and its effect on the mechanism of trastuzumab resistance.


Assuntos
Neoplasias da Mama , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias da Mama/metabolismo , Caderinas/genética , Linhagem Celular Tumoral , Feminino , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Células MCF-7 , Proteômica , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
2.
Eur J Cancer ; 45(7): 1265-1273, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19167213

RESUMO

Preclinical studies have shown the potential antitumour efficacy of monoclonal antibodies (MAbs) directed to the epidermal growth factor receptor (EGFR). In this report, we investigated the cytotoxic effects of the MAb matuzumab (EMD 72000) towards A431 cells and compared it to cetuximab. While cetuximab induced cell cycle arrest and inhibited A431 cell proliferation, matuzumab did not. Both MAbs inhibited growth factor induced EGFR, HER2 and AKT phosphorylation; however, only cetuximab inhibited ERK 1/2 phosphorylation. Taken together, the data indicate that each antibody may elicit different responses on EGFR downstream signalling pathways with a distinct impact on A431 cell line survival. When combined, MAbs synergistically inhibited cell proliferation and induced EGFR down-regulation with a strong inhibition of ERK1/2 and AKT phosphorylation. In addition, both MAbs efficiently inhibited VEGF expression and induced ADCC, highlighting their therapeutic potential in vivo when used either as a single agent or in combination.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Anticorpos Monoclonais Humanizados , Western Blotting , Proliferação de Células/efeitos dos fármacos , Cetuximab , Regulação para Baixo , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Flavonoides/farmacologia , Humanos , Fosforilação , Ligação Proteica , Fator A de Crescimento do Endotélio Vascular/metabolismo
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