The effects of retinoic acid on the Insulin-like growth factor axis in primary tissue culture from hyperparathyroidism

Wong, C. K., Lai, T., Holly, M. P., Wheeler, M. H., Stewart, Claire E. and Farndon, J. R. (2006) The effects of retinoic acid on the Insulin-like growth factor axis in primary tissue culture from hyperparathyroidism. World Journal of Surgery, 30 (5). pp. 714-720. ISSN 1432-2323

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Abstract

Background The importance of the IGF system in HPT has been previously demonstrated. Additionally, the role of vitamin A in HPT has been reported. Retinoic acid (RA), a derivative of vitamin A, is a ligand for the IGF II receptor (IGF2R). We have evaluated the interactions of RA with the IGF system in a primary parathyroid cell culture model. Materials and Methods Primary cell cultures were prepared from nine patients. Following adhesion, the cells were transferred to serum-free medium and dosed once with growth factors ± RA for 96 hours. Proliferation was assessed by measuring tritiated thymidine incorporation. Results Compared with the control group (100%), both IGF I and II increased DNA synthesis significantly. Retinoic acid significantly reduced the basal DNA synthesis to 82.2% ± 4.2% compared with control (P < 0.05). Retinoic acid ×10−5 M completely abrogated the proliferative actions of IGF II (70.2% ± 9.7%, P < 0.05) but had no significant effect on the IGF I response (P > 0.05). To evaluate the role of IGF2R or IGFBPs in mediating the actions of RA, the IGF II analogs [Leu27]IGF II (10–20-fold reduced IGF I receptor affinity) and des(1–6) IGF II (lower IGFBP binding affinity) were used. The IGF II inhibitory effect of RA was enhanced in the presence of analogs [Leu27]IGF II (P = 0.052) but not with des(1–6)IGF II (P > 0.05), compared with wild-type IGF II. Conclusions These data implicate a novel antiproliferative role for RA in enhancing the pericellular clearance of IGF II via the IGF2R preventing ligand activation of the IGF I receptor. This may have broader implications for RA effects in other tumors.