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Endocrinology Vol. 141, No. 7 2548-2556
Copyright © 2000 by The Endocrine Society

ARTICLES

1{alpha},25-Dihydroxyvitamin D3 Inhibits Prostate Cancer Cell Growth by Androgen-Dependent and Androgen-Independent Mechanisms1

Xiao-Yan Zhao, Donna M. Peehl, Nora M. Navone and David Feldman

Departments of Medicine (X.-Y.Z., D.F.) and Urology (D.M.P.), Stanford University School of Medicine, Stanford, California 94305; and Department of GU Medical Oncology, University of Texas M. D. Anderson Cancer Center (N.M.N.), Houston, Texas 77030

Address all correspondence and requests for reprints to: David Feldman, M.D., Division of Endocrinology, Room S-005, Stanford University Medical Center, Stanford, California 94305-5103. E-mail: feldman{at}cmgm.stanford.edu

We recently reported that 1{alpha},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 5{alpha}-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 µM) 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.




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