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Endocrinology Vol. 138, No. 5 2021-2032
Copyright © 1997 by The Endocrine Society

Articles

Up-Regulation of Insulin/Insulin-Like Growth Factor-I Hybrid Receptors during Differentiation of HT29-D4 Human Colonic Carcinoma Cells1

Françoise L. Garrouste, Maryse M. Remacle-Bonnet, Maxime M.-A. Lehmann, Jacques L. Marvaldi and Gilbert J. Pommier

Unité Interactions entre Systèmes Protéiques et Différenciation dans la Cellule Tumorale, CNRS URA 1924, Faculté de Médecine, Marseille, France

Address all correspondence and requests for reprints to: Dr. Gilbert J. Pommier, URA CNRS 1924, Faculté de Médecine, 27 boulevard Jean Moulin, 13385 Marseille Cedex 5, France.

To assess the autocrine function of insulin-like growth factor II (IGF-II) in the balance of proliferation and differentiation in HT29-D4 human colonic cancer cells, we studied the expression of IGF-I receptors (IGF-IR) and insulin receptors (IR) in relation to the state of cell differentiation. IGF-IR and IR were expressed in both undifferentiated and enterocyte-like differentiated HT29-D4 cells. IGF-IR had two isoforms with a 97-kDa and a 102-kDa ß-subunit. In addition, HT29-D4 cells expressed hybrid receptors (HR) formed by the association of two {alpha}ß heterodimers from both IR and IGF-IR. HR were evidenced through 1) inhibition of IGF-I binding by the B6 anti-IR antibody and 2) immunoprecipitation with the {alpha}-IR3 anti-IGF-IR antibody, which revealed an additional 95-kDa IR ß-subunit that disappeared when the heterotetrameric receptor was dissociated by disulfide reduction into {alpha}ß heterodimers before immunoprecipitation. Like IGF-IR, HR had a high affinity for IGF-I (Kd, ~1.5 nM), but did not bind insulin significantly; the latter interacted with the native IR only (Kd, ~4 nM). In the differentiated HT29-D4 cell monolayer, all receptor species were strongly polarized (>97%) toward the basolateral membrane. Moreover, HT29-D4 cell differentiation was accompanied by an approximately 2-fold increase in the number of IR, whereas the number of IGF-I-binding sites was unaltered. However, in differentiated HT29-D4 cells, ~55% of the latter were involved in HR vs. ~20% in undifferentiated HT29-D4 cells. Thus, HT29-D4 cell differentiation is characterized by an up-regulation (~3-fold) of the level of HR coupled to a down-regulation (~40%) of the level of native tetrameric IGF-IR. Alterations were induced early during the cell differentiation process, i.e. 5 days postconfluence, and remained unchanged for at least 21 days. Taken together, these results suggest that the IGF-II autocrine loop in HT29-D4 cells may trigger distinct signaling pathways if it activates native IGF-IR, which predominate in undifferentiated cells, or if it activates HR, which are up-regulated in differentiated cells.




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