S179D prolactin sensitizes human prostate cancer cells such that physiological concentrations of 1, 25 dihydroxy vitamin D3 result in growth inhibition and cell death.
BACKGROUND
S179D Prolactin (PRL) is a molecular mimic of naturally phosphorylated human PRL which has been shown to inhibit the growth of human prostate cancer cells both in vitro and when grown as tumors in nude mice.


METHODS
In the current study, we have investigated the potential interplay between S179D PRL and 1,25 dihydroxy vitamin D3 (1,25D) in the inhibition of prostate cancer cell growth by incubating cells under circumstances where each hormone alone has no effect.


RESULTS
Incubation of DU145 or PC3 cells in 100 pM 1,25D or 10 nM S179D PRL for 3 days showed no effect of each alone on expression of the vitamin D receptor (VDR), or the cell cycle regulatory protein p21, or on cell number. Incubation in both together increased expression of the VDR and p21 two to threefold. This co-operative effect was reproduced when activation of the p21 promoter was analyzed using a p21-luciferase (p21-luc) construct. Elimination of the VDR response element from p21-luc eliminated response to the hormone combination, showing that the effect on p21 was through the VDR. Most importantly, S179D PRL sensitized the cells to 1,25D such that there was a concentration-related reduction in cell number versus controls between 40 and 160 pM. At least part of this effect was via the induction of cell death.


CONCLUSIONS
These results suggest that combined anti-tumor therapy may be very efficacious and that the dose of 1,25D required may be below the range that results in hypercalcemia.
Division of Biomedical Sciences, University of California, Riverside, California 92521-0121, USA.
Wei
W
Wu
Laura
L
Zanello
Ameae M
AM
Walker
D015153:Blotting, Western; D002112:Calcifediol / Q000494:pharmacology*; D002452:Cell Count; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008297:Male; D011388:Prolactin / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000378:metabolism; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004338:Drug Combinations; D018167:Receptors, Calcitriol; D011981:Receptors, Prolactin; D011994:Recombinant Proteins; C422171:prolactin, Asp(179)-; D011388:Prolactin; D002112:Calcifediol