Calcitriol‐induced prostate‐derived factor: Autocrine control of prostate cancer cell growth

Calcitriol (1α,25‐dihydroxycholecalciferol) seems to play an important role in the complex control of prostate cell growth. It inhibits proliferation and induces differentiation and apoptosis in prostate cancer cells. However, the molecular mechanisms of the antiproliferative activity of calcitriol are not completely understood. The expression of prostate‐derived factor (PDF), a member of the transforming growth factor‐β (TGF‐β) superfamily, has been shown to be associated with proapoptotic and antimitotic activities. We show that calcitriol induces PDF expression in LNCaP human prostate cancer cells in a concentration‐ and time‐dependent manner. In LNCaP cells, the suppression of cell growth by calcitriol is accompanied by stimulation of PDF mRNA and protein synthesis. Human recombinant PDF inhibits LNCaP cell growth. We do not detect any effect of PDF‐specific antibody on the basal growth of LNCaP cells, but this antibody partially reverses the suppression of LNCaP cell growth by calcitriol, suggesting that the effect of calcitriol on cell growth is at least partially mediated by PDF. In PC‐3 cells, which are less responsive to the growth‐inhibitory effect of calcitriol, it has no effect on PDF expression. We do not detect an effect of recombinant PDF on SMAD phosphorylation in LNCaP cells, but ERK1/2 kinases are transiently phosphorylated in response to PDF, which suggests that in LNCaP cells PDF may exert its action through pathway alternative to the classical TGF‐β signaling pathway. The present study describes the regulation of PDF, the proapoptotic protein of the TGF‐β superfamily, by calcitriol in androgen‐responsive prostate cancer cells. This is a new link between calcitriol and growth factors of TGF‐β superfamily in the control of prostate cell growth. © 2004 Wiley‐Liss, Inc.