1alpha,25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms

Endocrinology. 2000 Jul;141(7):2548-56. doi: 10.1210/endo.141.7.7549.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgens / pharmacology
  • Androgens / physiology*
  • Anilides / pharmacology
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Humans
  • Ligands
  • Male
  • Nitriles
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Receptors, Androgen / metabolism
  • Receptors, Calcitriol / metabolism
  • Tosyl Compounds
  • Up-Regulation
  • Vitamin D / analogs & derivatives*
  • Vitamin D / pharmacology

Substances

  • Androgen Antagonists
  • Androgens
  • Anilides
  • Antineoplastic Agents
  • Ligands
  • Nitriles
  • Receptors, Androgen
  • Receptors, Calcitriol
  • Tosyl Compounds
  • dihydroxy-vitamin D3
  • Vitamin D
  • bicalutamide
  • Prostate-Specific Antigen