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Inhibition of Growth and Increased Expression of Insulin-Like Growth Factor-Binding Protein-3 (IGFBP-3) and -6 in Prostate Cancer Cells Stably Transfected with Antisense IGFBP-4 Complementary Deoxyribonucleic Acid¹

Research Service, Department of Veterans Affairs Puget Sound Health Care System (R.H.D., C.S., K.T., S.R.P.), Tacoma, Washington 98493; and Department of Medicine, University of Washington (R.H.D., S.R.P.), Seattle, Washington 98195

Address all correspondence and requests for reprints to: Dr. Rolf H. Drivdahl, Research Service (151), Veterans Affairs Medical Center, American Lake, Tacoma, Washington 98493. E-mail: drivdahl.rolf_h{at}seattle.va.gov

Insulin-like growth factor-binding proteins (IGFBPs) both stimulate and inhibit IGF activity, and in the M12 prostate cancer cell line, overexpression of IGFBP-4 was shown to delay tumorigenesis while decreasing the production of IGFBP-2. We have performed the reverse experiment, inhibition of IGFBP-4 expression with antisense complementary DNA, in two prostate tumor cell lines, ALVA-31 and M12. Expression of antisense messenger RNA transcripts was verified by RNase protection assays, and inhibition of mature IGFBP-4 in cell medium was demonstrated by Western blotting. Both transfected lines (ALVA-31asBP4 and M12asBP4) proliferated more slowly in monolayer culture than parental controls. Colony formation in soft agar was strongly inhibited in both cases, and the rate of tumor formation and growth in male athymic nude mice injected with M12asBP4 was markedly reduced relative to that in mice receiving M12 control cells. Apoptosis induced by the topoisomerase inhibitor etoposide was also enhanced in transfected cells. The effects on colony formation in soft agar and tumor formation in mice were maintained for the duration of the experiments, in contrast to the delayed growth observed in the previous study of IGFBP-4 overexpression. A significant difference was found in the patterns of IGFBP expression; production of both messenger RNA and protein for IGFBP-3 and IGFBP-6 was greatly increased in the M12asBP4 and ALVA31asBP4 cell lines. Up-regulation of these binding proteins has been observed in association with actions of 1,25-dihydroxyvitamin D₃ in prostate cancer cells, and the data suggest a role for IGFBP-3 and IGFBP-6 in the suppression of prostate tumor cell growth.

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