OVEREXPRESSION OF AN INHIBITORY INSULIN-LIKE-GROWTH-FACTOR BINDING-PROTEIN (IGFBP), IGFBP-4, DELAYS ONSET OF PROSTATE TUMOR-FORMATION

Insulin-like growth factor (IGF) binding proteins (IGFBPs) have been s hown to either inhibit or enhance the action of IGF, or act in an IGF- independent manner in the prostate. We have overexpressed the IGF-inhi bitory IGFBP-4 in the malignant M12 prostate epithelial cell line to d etermine the effects on tumor formation and apoptosis. Overexpression was determined by Not-them, Western immunoblot and Western radioligand blot analysis. IGF induced proliferation was reduced in the IGFBP-4 t ransfected cells compared with control cells (P less than or equal to 0.01). Colony formation in soft agar was significantly inhibited up to 14 days after plating in the IGFBP-4 transfected cells when compared with the M12 controls (P less than or equal to 0.01): however, in the presence of des(1-3)IGF-I, there was no significant difference between the control and IGFBP-4 transfectants in colony formation in soft, ag ar. Apoptosis in an IGFBP-4 transfected cell Line was significantly in creased in response to induction by B-hydroxyurea compared with the co ntrol Line. When injected sc into male athymic/nude mice, a marked del ay was noted in tumor formation in animals receiving IGFBP-4 transfect ed cells (P less than or equal to 0.01). Interestingly, IGFBP-2 protei n levels were reduced in the conditioned media of all IGFBP-4 transfec ted cell cultures. These data indicate that an inhibitory IGFBP may si gnificantly delay the growth of malignant prostate epithelial cells an d enhance the sensitivity of these cells to apoptosis.