Calcitriol and TO-901317 Interact in Human Prostate

Abstract: Vitamin D receptor (VDR) and liver X receptor (LXR) are nuclear receptors, which regulate gene transcription upon binding of their specifi c ligands. VDR seems to play a role in the regulation of prostate cancer cell proliferation. ATP-binding cassette transporter A1 (ABCA1) is known to be a target gene of LXR and it has been reported to be inhibited by androgen and to be involved in the regulation of LNCaP proliferation. We fi nd that calcitriol (1α,25(OH)2D3) inhibits both basal and a LXR agonist, TO-901317, induced ABCA1 mRNA expression but has no effect on the mRNA expression of ATP-binding cassette transporter G1 (ABCG1), LXRα nor LXRβ. TO-901317 increases both basal and calcitriol induced 25-hydroxyvitamin D3-24-hydroxylase (CYP24) mRNA expression and it slightly but signifi cantly inhibits VDR mRNA expression. The inhibition of ABCA1 by calcitriol appears to be androgen-independent. Cell growth assay shows that when each of calcitriol and 5α-dihydrotestosterone (DHT) was co-treated with ABCA1 blocker, glybenclamide, cell-growth is signifi cantly decreased compared to their own treatments respectively. Our study suggests a possible interaction between calcitriol and TO-901317 in LNCaP cells. Alike DHT, the inhibition of ABCA1 by calcitriol may be involved in its regula-tion of LNCaP growth