Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues.

Autor: Lundby A; Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen N, Denmark., Bolvig P; Diabetes Research Unit, Novo Nordisk A/S, Novo Nordisk Park, 2760, Maaloev, Denmark., Hegelund AC; Diabetes Research Unit, Novo Nordisk A/S, Novo Nordisk Park, 2760, Maaloev, Denmark., Hansen BF; Diabetes Research Unit, Novo Nordisk A/S, Novo Nordisk Park, 2760, Maaloev, Denmark., Worm J; Diabetes Research Unit, Novo Nordisk A/S, Novo Nordisk Park, 2760, Maaloev, Denmark., Lützen A; Diabetes Research Unit, Novo Nordisk A/S, Novo Nordisk Park, 2760, Maaloev, Denmark., Billestrup N; Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen N, Denmark., Bonnesen C; Diabetes Research Unit, Novo Nordisk A/S, Novo Nordisk Park, 2760, Maaloev, Denmark., Oleksiewicz MB; Centre for Biosecurity and Biopreparedness, Statens Serum Institute, Artillerivej 5, 2300, Copenhagen S, Denmark.
Jazyk: angličtina
Zdroj: Journal of applied toxicology : JAT [J Appl Toxicol] 2015 Jul; Vol. 35 (7), pp. 842-50. Date of Electronic Publication: 2014 Nov 21.
DOI: 10.1002/jat.3082
Abstrakt: There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF-IR. Insulin exhibited mitogenicity EC(50) values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA-mediated knockdown of IR and IGF-IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF-IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF-IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF-I in cells expressing more IR than IGF-IR, the hyper-mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper-mitogenic effect of X10 involves the IR as well as the IGF-IR. These results are relevant for preclinical safety assessment of developmental insulin analogues.
(Copyright © 2014 John Wiley & Sons, Ltd.)
Databáze: MEDLINE
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