1alpha,25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms.
We recently reported that 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits the growth of the LNCaP human prostate cancer cell line by an androgen-dependent mechanism. In the present study we examined the actions and interactions of 1,25-(OH)2D3 and the androgen 5alpha-dihydrotestosterone (DHT) on two new human prostate cancer cell lines (MDA), MDA PCa 2a and MDA PCa 2b. Scatchard analyses revealed that both cell lines express high affinity vitamin D receptors (VDRs) with a binding affinity (Kd) for [3H]1,25-(OH)2D3 of 0.1 nM. However, the MDA cell lines contain low affinity androgen receptors (ARs) with a Kd of 25 nM for [3H]DHT binding. This is 50-fold lower than the AR in LNCaP cells (Kd = 0.5 nM). Their response to DHT is greatly reduced; 2a cells do not respond to 100 nM DHT, and 2b cells show a modest response at that high concentration. 1,25-(OH)2D3 causes significant growth inhibition in both MDA cell lines, greater (for 2b cells) or lesser (for 2a cells) than that in the LNCaP cell line. Moreover, 1,25-(OH)2D3 significantly up-regulates AR messenger RNA in all three cell lines, as shown by Northern blot analysis. The growth inhibitory effect of 1,25-(OH)2D3 on LNCaP cells is blocked by the pure antiandrogen, Casodex, as we previously reported. However, Casodex (at 1 microM) did not block the antiproliferative activity of 1,25-(OH)2D3 in MDA cells. In conclusion, the growth inhibitory action of 1,25-(OH)2D3 in the MDA cell lines appears to be androgen independent, whereas the actions of 1,25-(OH)2D3 in LNCaP cells are androgen dependent. Most importantly, the MDA cell lines, derived from a bone metastasis of human prostate carcinoma, remain sensitive to 1,25-(OH)2D3, a finding relevant to the therapeutic application of vitamin D and its low calcemic analogs in the treatment of advanced prostate cancer.
Zhao
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Department of Medicine, Stanford University School of Medicine, California 94305, USA.
Peehl
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Navone
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Feldman
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D
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology / Q000502:physiology*; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D009570:Nitriles; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D014105:Tosyl Compounds; D015854:Up-Regulation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D008024:Ligands; D009570:Nitriles; D011944:Receptors, Androgen; D018167:Receptors, Calcitriol; D014105:Tosyl Compounds; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C053541:bicalutamide; D017430:Prostate-Specific Antigen