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1.
Br J Cancer ; 106(8): 1406-14, 2012 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-22491422

RESUMO

BACKGROUND: In addition to the mutational status of KRAS, the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG) might function as bona fide biomarkers of cetuximab (Ctx) sensitivity for most EGFR-driven carcinomas. METHODS: Lentivirus-delivered small hairpin RNAs were employed to specifically reduce AREG or EREG gene expression in wild-type KRAS A431 squamous cell carcinoma cells. Colony-forming assays were used to monitor the impact of AREG and EREG knockdown on Ctx efficacy. Amphiregulin and EREG protein expression levels were assessed by quantitative ELISA in parental A431 cells and in pooled populations of A431 cells adapted to grow in the presence of Ctx. A phosphoproteomic platform was used to measure the relative level of phosphorylation of 42 distinct receptor tyrosine kinases before and after the acquisition of resistance to Ctx. RESULTS: Stable gene silencing of either ligand was found to notably reduce the expression of the other ligand. Parental A431 cells with normal expression levels of AREG/EREG exhibited significantly increased growth inhibition in response to Ctx, compared with derivatives that are engineered to produce minimal AREG/EREG. The parental A431 cells acutely treated with Ctx exhibited reduced basal expression levels of AREG/EREG. Pooled populations of Ctx-resistant A431 cells expressed significantly lower levels of AREG/EREG and were insensitive to the downregulatory effects of Ctx. Phosphoproteomic screen identified a remarkable hyperactivation of FGFR3 in Ctx-resistant A431 cells, which gained sensitivity to the cytotoxic and apoptotic effects of the FGFR3 TK inhibitor PD173074. The A431 parental cells acutely treated with Ctx rapidly activated FGFR3 and their concomitant exposure to Ctx and PD173074 resulted in synergistic apoptosis. CONCLUSION: Cross-suppression of AREG/EREG expression may explain the tight co-expression of AREG and EREG, as well as their tendency to be more highly expressed than other EGFR ligands to determine Ctx efficacy. The positive selection for Ctx-resistant tumour cells exhibiting AREG/EREG cross-suppression may have an important role in the emergence of Ctx resistance. As de-repression of FGFR3 activity rapidly replaces the loss of EGFR-ligand signalling in terms of cell proliferation and survival, combinations of Ctx and FGFR3-targeted drugs may be a valuable strategy to enhance the efficacy of single Ctx while preventing or delaying acquired resistance to Ctx.


Assuntos
Anticorpos Monoclonais/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Crescimento Epidérmico/antagonistas & inibidores , Receptores ErbB/metabolismo , Glicoproteínas/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Anfirregulina , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cetuximab , Família de Proteínas EGF , Fator de Crescimento Epidérmico/biossíntese , Fator de Crescimento Epidérmico/genética , Epirregulina , Técnicas de Silenciamento de Genes , Glicoproteínas/biossíntese , Glicoproteínas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ligantes , Pirimidinas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Relação Estrutura-Atividade , Células Tumorais Cultivadas
2.
Curr Mol Med ; 10(7): 674-91, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20712585

RESUMO

A whole new area of investigation has emerged recently with regards to the anti-diabetic drug metformin and breast cancer. Metformin's anti-breast cancer actions, observed in population studies, in rodents and in cultured tumour cells, are especially encouraging because they attack not only the most common bulk of the tumour cells but also the more rare tumour-initiating stem cells. Here, we illustrate the multifaceted and redundant mechanisms through which metformin-reprogrammed energy metabolism at both the organismal and cellular levels constitutes a novel and valuable strategy to prevent and treat breast cancer disease.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Metabolismo Energético , Insulina/fisiologia , Metformina/uso terapêutico , Glicemia , Neoplasias da Mama/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glicólise , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/fisiologia , Fosforilação Oxidativa , Receptor de Insulina/metabolismo , Somatomedinas/metabolismo
3.
Av. diabetol ; 26(2): 79-89, mar.-abr. 2010. ilus
Artigo em Inglês | IBECS | ID: ibc-85850

RESUMO

The possibility exists to adopt insulin reduction for preventive and therapeuticpurposes in breast cancer. In this regard, recent interest has been focused onthe insulin sensitizer metformin, a biguanide derivative that significantly reducesbreast cancer incidence and improves breast cancer patient’s survival intype 2 diabetics. The ability of metformin to activate AMP-activated proteinkinase (AMPK), a key regulator of energy balance in the single cell and thewhole organism, largely explains metformin’s anti-breast cancer activity. Here,we review the multifaceted and redundant mechanisms through which metformin-reprogrammed energy metabolism at both the organismal and the cellularlevel may constitute a novel and valuable strategy to prevent and treatbreast cancer disease(AU)


Assuntos
Humanos , Masculino , Feminino , Metformina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Biologia Molecular/métodos , Células-Tronco , Resistência à Insulina/fisiologia , Insulina/administração & dosagem , Lipogênese , Metformina/metabolismo , Metformina/farmacologia , Metformina/farmacocinética , Dieta para Diabéticos/métodos , Dieta , Mitose
5.
Clin. transl. oncol. (Print) ; 11(7): 455-459, jul. 2009. ilus
Artigo em Inglês | IBECS | ID: ibc-123658

RESUMO

The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients (AU)


Assuntos
Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , /uso terapêutico , Proteínas Quinases/metabolismo , Quinazolinas/uso terapêutico , /antagonistas & inibidores , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Modelos Biológicos , /metabolismo , Serina-Treonina Quinases TOR
7.
Biochim Biophys Acta ; 1417(1): 32-6, 1999 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-10076033

RESUMO

Site-directed mutants of yeast ATPase were previously studied after introduction of mutant alleles into a yeast strain where these alleles were constitutively expressed while the expression of the wild-type chromosomal ATPase gene was turned off. As a functional H+ pump is essential, strong selective pressure leads to the accumulation of revertants during growth of cells harboring variants with low activity. Thus, constitutive expression of the mutant gene can select phenotypes which reflect events such as gene conversion or reversion. We have therefore re-evaluated the phenotypes of non-dominant lethal alleles in an alternative set of conditional expression systems. We show that eight of 11 previously described site-directed mutations behave as recessive lethal alleles.


Assuntos
ATPases Translocadoras de Prótons/genética , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Membrana Celular/enzimologia , Mutagênese Sítio-Dirigida , Mutação , Fenótipo , Plasmídeos , ATPases Translocadoras de Prótons/biossíntese , Saccharomyces cerevisiae/enzimologia
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