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 shown to either inhibit or enhance the action of IGF, or act in an IGF-independent manner in the prostate. We have overexpressed the IGF-inhibitory IGFBP-4 in the malignant M12 prostate epithelial cell line to determine the effects on tumor formation and apoptosis. Overexpression was determined by Northern, Western immunoblot and Western radioligand blot analysis. IGF-induced proliferation was reduced in the IGFBP-4 transfected cells compared with control cells (P < or = 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 < or = 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 agar. Apoptosis in an IGFBP-4 transfected cell line was significantly increased in response to induction by 6-hydroxyurea compared with the control line. When injected s.c. into male athymic/nude mice, a marked delay was noted in tumor formation in animals receiving IGFBP-4 transfected cells (P < or = 0.01). Interestingly, IGFBP-2 protein levels were reduced in the conditioned media of all IGFBP-4 transfected cell cultures. These data indicate that an inhibitory IGFBP may significantly delay the growth of malignant prostate epithelial cells and enhance the sensitivity of these cells to apoptosis.
Damon
S E
SE
Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Tacoma, Washington 98493, USA.
Maddison
L
L
Ware
J L
JL
Plymate
S R
SR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division; D002461:Cell Line, Transformed; D017077:Culture Media, Conditioned; D004847:Epithelial Cells; D015870:Gene Expression; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D014162:Transfection
D017077:Culture Media, Conditioned; D018974:Insulin-Like Growth Factor Binding Protein 4