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A Shukla, Hormones and Signal Transduction, German Cancer Research Center, Heidelberg, Germany
J Grisouard, Heidelberg, Germany
V Ehemann, Pathology, Heidelberg University, Heidelberg, Germany
A Hermani, Heidelberg, Germany
H Enzmann, Federal Institute for Drugs and Medical Devices, Bonn, Germany
D Mayer, Hormones and Signal Transduction, German Cancer Research Center, Heidelberg, 69120, Germany

Correspondence: Doris Mayer, Email: d.mayer{at}dkfz.de

Abstract

Insulin and insulin analogs stimulate proliferation of human mammary epithelial cells. We identified and analyzed the signaling pathways related to cell proliferation induced by regular insulin and by four insulin analogs currently approved for therapeutical use. Benign and malignant mammary cell lines showing different insulin receptor and IGF-I receptor (IGF-IR) expression patterns were studied. Cell proliferation was studied by crystal violet staining and BrdU FACS analysis. Activation of insulin and IGF signaling pathways was studied by analysis of the phosphorylation status of IGF-IR and of key signaling proteins of the phosphoinositide 3-kinase (PI3K)/Akt and MAP kinase pathways, by use of specific PI3K and MAP kinase inhibitors, and by silencing of insulin receptor and IGF-IR. Lantus stimulated the growth of MCF7 cells, which show high IGF-IR/insulin receptor ratio, significantly at 0.3 nanomol l-1, while regular insulin (Actrapid, bovine insulin) and other insulin analogs (Novorapid, Humalog, Levemir) stimulated cell growth at 1.5 to 15 nanomol l-1 concentrations. No difference between Lantus and the other insulin analogs was observed regarding growth stimulation of MCF10A cells showing low IGF-IR / insulin receptor ratio. Growth stimulation of MCF7 cells by Lantus was mainly due to strong activation of the IGF-IR and the MAP kinase pathway. Regular insulin and other insulin analogs tested activated mainly the insulin receptor and the PI3K/Akt pathway. We conclude that unlike regular insulin and other insulin analogs, Lantus strongly activates the IGF-IR and the MAP kinase pathway in MCF7 cells and is a strong mitogen for cells characterized by a high IGF-IR/insulin receptor ratio.