RESUMO
Insulin analogues are widely used in clinical practice. Modifications on the insulin molecular structure can affect the affinity and activation towards two closely related receptor tyrosine kinases: the insulin receptor (INSR) and the insulin-like growth factor 1 receptor (IGF1R). A switch towards higher IGF1R affinity is likely to emphasize mitogenesis rather than glucose metabolism. Relevant well-validated experimental tools to address the insulin analogue activation of either INSR or IGF1R are missing. We have established a panel of human MCF-7 breast cancer cell lines either ectopically expressing the INSR (A or B isoform) in conjunction with a stable knockdown of the IGF1R or ectopically expressing the IGF1R in conjunction with a stable knockdown of the INSR. In these cell lines, we systematically evaluated the INSR and IGF1R receptor activation and downstream mitogenic signalling of all major clinical relevant insulin analogues in comparison with insulin and IGF1R. While most insulin analogues primarily activated the INSR, the mitogenic activation pattern of glargine was highly similar to IGF1 and insulin AspB10, known to bind IGF1R and induce carcinogenesis. Yet, in a long-term proliferation assay, the proliferative effect of glargine was not much different from regular insulin or other insulin analogues. This was caused by the rapid enzymatic conversion into its two metabolic active metabolites M1 and M2, with reduced mitogenic signalling through the IGF1R. In summary, based on our new cell models, we identified a similar mitogenic potency of insulin glargine and AspB10. However, rapid enzymatic conversion of glargine precludes a sustained activation of the IGF1R signalling pathway.
Assuntos
Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Engenharia Genética , Hipoglicemiantes/toxicidade , Insulina/toxicidade , Antígenos CD/genética , Antígenos CD/metabolismo , Biotransformação , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Engenharia Genética/métodos , Humanos , Hipoglicemiantes/metabolismo , Insulina/análogos & derivados , Insulina/metabolismo , Insulina Glargina/toxicidade , Células MCF-7 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Receptor IGF Tipo 1 , Receptor de Insulina/agonistas , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptores de Somatomedina/agonistas , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , TransfecçãoRESUMO
Rosai-Dorman disease (RDD) is a rare disorder of proliferative histiocytes with an unknown etiology. It is also known as sinus histiocytosis with massive lymphadenopathy. Most patients present with painless cervical lymphadenopathy due to accumulation of histiocytes in the lymph nodes, often in conjunction with fever, elevated leukocyte count and erythrocyte sedimentation rate. Isolated skeletal involvement is very rare.