Insulin like growth factor I is an autocrine regulator of human colon cancer cell differentiation and growth.
The polyanionic compound suramin triggers enterocyte-like differentiation of the human colic adenocarcinoma cell clone HT29-D4. We now demonstrate that suramin interferes with the binding of IGF-I to its receptor at the surface of HT29-D4 cells. Half-maximum inhibition of 125I-IGF-I binding was obtained in the presence of 25 micrograms/ml suramin. Moreover, the drug was able to dissociate 125I-IGF previously bound to its cell surface receptor. Affinity labeling HT29-D4 cells were cultured in the presence of 10 micrograms/ml of alpha-IR3, a monoclonal antibody directed against the binding site of IGF-I, an inhibition of cell proliferation and a stimulation of cell differentiation was observed. After 10 days of treatment with alpha-IR3, HT29-D4 cells formed a regular monolayer of enterocyte-like cells exhibiting an apical brush border and tight junctions delimiting two domains of the plasma membrane (apical and basolateral). Furthermore, we show that IGF-I significantly increased the initial rate of glucose uptake by HT29-D4 cells, while we have previously shown that suramin decreased glucose consumption. From these data we conclude that IGF-I secreted by the cells themselves, stimulates proliferation of HT29-D4 cells via an autocrine mechanism. Blockade of this stimulation by suramin or by a specific monoclonal antibody inhibits cell growth, glucose uptake and triggers the process of enterocytic differentiation.
Baghdiguian
S
S
INSERM U270, Faculté de Médecine, Marseille, France.
Verrier
B
B
Gerard
C
C
Fantini
J
J
D001692:Biological Transport / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016764:Cell Polarity; D003110:Colonic Neoplasms / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D017451:Receptors, Somatomedin; D013498:Suramin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D013498:Suramin; D007334:Insulin-Like Growth Factor I; D005947:Glucose