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Potential Autocrine Role of Insulin-like Growth Factor II during Suramin-induced Differentiation of HT29-D4 Human Colonic Adenocarcinoma Cell Line¹

Laboratoire d'Immunopathologie, Faculté de Médecine [G. J. P., F. L. G., F. E. A.], and Institut de Chimie Biologique, CNRS-URA 202, Faculté des Sciences [M. R., J. L. M., M. M. R. B.], Marseille, France

Suramin, a drug that binds to several types of growth factors, has been previously shown to induce the enterocyte-like differentiation of HT29-D4 human colonic adenocarcinoma cells, suggesting that growth factors are involved in such a process. Undifferentiated HT29-D4 cells release insulin-like growth factor II (IGF-II) into the culture medium that is totally complexed to heterogeneous IGF binding proteins (IGFBP) expressing high affinities for this growth factor (K_da = 0.02 mM and K_db = 1.4 nM). These complexes do not allow IGF-II to bind to HT29-D4 cell surface type I IGF receptors, as evidenced by using ¹²⁵I-IGF-II-IGFBP complexes. However, the addition of 40–100 µg/ml suramin, i.e., concentrations identical to the ones that are able to induce HT29-D4 cell differentiation, induces the release of IGF-II from IGF-II-IGFBP complexes, thereby allowing IGF-II to bind to the cell surface receptors. At such concentrations, suramin is indeed unable to alter IGF-II binding to HT29-D4 cells, a capacity that is observed only for concentrations higher than 200 µg/ml. Thus, suramin might have the unusual capacity to allow the establishment of an IGF-II autocrine loop involved in HT29-D4 cell differentiation. Consistent with this hypothesis is the fact that exogenously applied IGF-I (2.5 µg/ml) or agonist monoclonal antibody IR-3 (2.5 µg/ml), which can bypass IGFBP present in the culture medium, induces part of HT29-D4 cell differentiation that is characterized by an important carcinoembryonic antigen release and the induction of numerous intercellular cysts with microvilli.

¹ Supported by grants from the Association pour la Recherche sur le Cancer and Ligue Nationale Française contre le Cancer.

² To whom requests for reprints should be addressed, at Laboratoire d'Immunopathologie, Faculté de Médecine, 27, Boulevard Jean Moulin, 13385 Marseille Cedex 5, France.

Received 11/ 5/91. Accepted 3/20/92.

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