1,25-(OH)2 vitamin D3 (1,25-(OH)2 D), the active metabolite of vitamin D, exerts antiproliferative effects on a variety of tumor cells including prostate. This inhibition requires vitamin D receptors (VDRs) as well as downstream effects on the G1 to S phase checkpoint of the cell cycle. Recent data raise the possibility that androgen plays a role in the antiproliferative effects of 1,25-(OH)2 D in prostate cancer cells; however, this hypothesis has been difficult to test rigorously as the majority of prostate cancer cell lines (unlike human prostate tumors) lack androgen receptors (ARs). We utilized two different models of androgen-independent prostate cancer that express functional ARs and VDRs to evaluate a possible role of androgen in 1,25-(OH)2 D mediated growth inhibition. We stably introduced the AR cDNA into the human prostate cancer cell line ALVA 31, which expresses functional VDR but is relatively resistant to growth inhibition by 1,25-(OH)2 D. Neither ALVA-AR nor the control cells, ALVA-NEO, exhibited substantial growth inhibition by 1,25-(OH)2 D in the presence or absence of androgen. This observation suggests that the basis for the resistance of ALVA 31 to 1,25-(OH)2 D-mediated growth inhibition is not the lack of AR. The second model was LNCaP-104R1, an AR-expressing androgen independent prostate cancer cell line derived from androgen dependent LNCaP. 1,25-(OH)2 D inhibited the growth of LNCaP-104R1 cells in the absence of androgen and this effect was not blocked by the antiandrogen Casodex. As was observed in the parental LNCaP cells, this effect was correlated with G1 phase cell cycle accumulation and upregulation of the cyclin dependent kinase inhibitor (CKI) p27, as well as increased association of p27 with cyclin dependent kinase 2. These findings suggest that the antiproliferative effects of 1,25-(OH)2 D do not require androgen-activated AR but do involve 1,25-(OH)2 D induction of CKIs required for G1 cell cycle checkpoint control.
|Number of pages||11|
|Journal||Molecular and Cellular Endocrinology|
|State||Published - Jan 15 2002|
Bibliographical noteFunding Information:
We thank Drs Shutsung Liao and John Kokontis (University of Chicago) for providing the LNCaP-104R1 cells and Dr Michael McPhaul (University of Texas Southwestern) for providing the AR cDNA. This work was supported by grants from the NIEHS (Fellowship #F30 ES05910-02), Pfeiffer Research Foundation, American Institute for Cancer Research, Pharmaceutical Research and Manufacturers of America Foundation and US Department of Defense (DAMD-17-98-1-8525). This work is dedicated to the memory of Dr Gary Miller whose pioneering work on vitamin D and prostate cancer will continue to inspire researchers.
- Androgen independence
- Androgen receptor
- Cyclin dependent kinase inhibitor
- Vitamin D receptor
ASJC Scopus subject areas
- Molecular Biology