Insulin-like growth factor binding protein-3 is regulated by dihydrotestosterone and stimulates deoxyribonucleic acid synthesis and cell proliferation in LNCaP prostate carcinoma cells.
We have investigated the production and actions of a growth regulatory protein, insulin-like growth factor binding protein (IGFBP)-3, in the androgen-responsive prostate carcinoma cell line LNCaP. Confluent monolayers of cells secreted approximately 0.7 ng/ml IGFBP-3 over 24 h. Dihydrotestosterone (DHT, 10 nM) and 1,25-dihydroxyvitamin D3 (vitamin D, 10 nM) increased IGFBP-3 in media to 149 +/- 15% and 206 +/- 18% of control, respectively, when added separately, and to 453 +/- 28% of control when used in combination. IGFBP-2, secreted at approximately 25-fold higher concentrations than IGFBP-3, was increased 50% by 10 nM DHT, but there was no effect of vitamin D on IGFBP-2 production in the absence or presence of DHT. Cell-associated IGFBP-3, and immunoreactive IGFBP-3 species of 20 kDa and 30 kDa were also increased in response to vitamin D plus DHT. A combination of vitamin D and DHT increased DNA synthesis in LNCaP cells 3-fold, and this was at least partly mediated by endogenous IGFBP-3 because anti-IGFBP-3 IgG, but not nonimmune serum IgG, reduced the stimulatory effect of vitamin D and DHT from 293 +/- 11.6% to 161 +/- 30.7% of control levels (P < 0.0001). Basal and DHT plus vitamin D-stimulated thymidine incorporation was significantly increased by 50 ng/ml human plasma-derived purified IGFBP-3. After 4 days treatment with vitamin D plus DHT, or pure IGFBP-3, LNCaP cell numbers were increased relative to control. These results indicate a role for IGFBP-3 in the proliferation of androgen-responsive prostate carcinoma cells.
Martin
J L
JL
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia. janetlm@med.usyd.edu.au
Pattison
S L
SL
D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000096:biosynthesis*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000494:pharmacology
D004273:DNA, Neoplasm; D004338:Drug Combinations; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D013196:Dihydrotestosterone; D014807:Vitamin D; D007334:Insulin-Like Growth Factor I; D004247:DNA; D013936:Thymidine