A molecular mimic of phosphorylated prolactin markedly reduced tumor incidence and size when DU145 human prostate cancer cells were grown in nude mice.
Others have demonstrated the presence of an autocrine prolactin (PRL) growth loop in the normal human prostate. In this study we have used three human prostate cancer cell lines but have focused on the androgen-independent human prostate cancer cell line, DU145, to ask: (a) whether this autocrine growth loop is maintained beyond the loss of androgen sensitivity in the progression of prostate cancer; and (b) whether interruption of this growth loop by a PRL receptor antagonist, an S179D mutant PRL, could inhibit the formation of DU145-derived tumors. The autocrine loop was examined in most detail in the DU145 cell line but was demonstrated to be functional in all three of the lines by the reversible inhibition of growth in vitro by the S179D PRL receptor antagonist. To investigate the effect of S179D PRL on the growth of DU145 tumors in nude mice two sets of experiments were performed. In the first set, Alzet minipumps containing no PRL, wild-type (WT) PRL, or the S179D PRL (the last two delivering 4.56 microg/24 h and 4.26 microg/24 h, respectively), were implanted s.c. on day 1. On day 4, 5 x 10(6) DU145 cells were injected s.c. in the hindquarter. On day 22, the animals were killed, tumors were removed, measured, and subsequently fixed and processed for histological confirmation of tumor formation. The incidence of tumors in the no-PRL control group was 9/11 animals (82%). In the animals treated with WT PRL, the incidence was 8/10 (80%), whereas in the animals treated with the S179D PRL, the incidence was markedly reduced to 3/11 (27%). Although WT PRL had no effect on the incidence of tumors, the average size of the tumors increased from 25.8 +/- 5.99 mm(3) in controls to 66.66 +/- 18.06 mm(3) in WT PRL-treated animals. In the second set of experiments, 5 x 10(6) DU145 cells were injected on day 1. On day 18, Alzet minipumps containing no PRL, WT PRL, or S179D PRL were implanted. On day 42, the animals were killed and the tumors processed as before. S179D PRL caused a reduction in tumor size from 1731 +/- 283 mm(3) in the no-PRL controls to 1031 +/- 295 mm(3), whereas WT PRL slightly increased the size to 2118 +/- 630 mm(3). We conclude that PRL is used as an autocrine growth factor by human prostate cancer cells both in vitro and in vivo and that interruption of this growth loop in vivo inhibits tumor initiation and the growth of well-established tumors.
Xu
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Division of Biomedical Sciences, University of California, Riverside, California 92521, USA.
Kreye
E
E
Kuo
C B
CB
Walker
A M
AM
D000728:Androgens / Q000502:physiology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011388:Prolactin / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D011467:Prostate / Q000254:growth & development / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D017077:Culture Media, Conditioned; D006131:Growth Inhibitors; D011981:Receptors, Prolactin; C422171:prolactin, Asp(179)-; D011388:Prolactin