Abstract
Abstract It has been proposed that 1α,25(OH)2D3 can be used as a combination therapy with anti-androgens for the treatment of early stage and locally invasive prostate cancer. However, recent studies from our laboratory suggest that 1α,25(OH)2D3 mediated signaling may significantly interact with AR mediated cell survival pathways, and may reduce the efficacy of anti-androgen therapy in hormone replete prostate cancer patients. In LNCaP cells, 100µM bicalutamide induces the rapid degradation of the androgen receptor (AR) and apoptosis (as measured by Apo-BrdU staining) in the presence or absence of 5nM testosterone. In the absence of testosterone, addition of 100nM 1α,25(OH)2D3 has little or no effect on either parameter. However the effect of 1α,25(OH)2D3 is significantly altered in the presence of 5nM testosterone: the AR is stabilized and the induction of cell death is abrogated. To identify the underlying mechanism regulating these effects we have used microarray analysis to identify a set of genes that are differentially regulated by both 1α,25(OH)2D3 and testosterone. These genes can be binned into several ontologies, including cell cycle progression and apoptosis, metastasis and cell invasion, and membrane protein and vesicular trafficking. Treatment with 1α,25(OH)2D3 in LNCaP leads to a downregulation of aurora kinase B while the p15 mRNA level increases after treatment both in the presence and absence of testosterone. The mRNA levels of known VDR induced genes such as p21 and p27 are not altered under these conditions. In contrast, genes involved in the maintenance of intracellular calcium levels, such as TRPV6 and ITPR1 are affected and may further influence the activity of various Ca2+ responsive genes, including ANXA2 and STK17B. Upregulation of TRPV6 and ANXA2 have been reported to correlate with metastatic transformation in cancer cells while changes in ITPR1 and STK17B levels influence cell cycle progression and apoptosis. However, some of these genes do not appear to have consensus VDREs in the promoter, raising issues about the regulation of the steady state of RNA levels. miRNA array analysis identified 16 miRNAs that are differentially regulated by 1α,25(OH)2D3 and testosterone. These miRNAs have 8500 predicted target genes including TRPV6 and STK17B. The increase in mRNA of these two sequences may be the result of downregulation of hsa-miR-17 and hsa-miR-20ab by 1α,25(OH)2D3 in LNCaP cells, while the decrease in aurora kinase B mRNA level with treatment of 1α,25(OH)2D3 correlates with the increase in hsa-miR-29ab. These results suggest that 1α,25(OH)2D3 can affect gene expression by regulating transcription through VDREs and by modulating the levels of specific microRNAs, or both. Furthermore, changes in these genes may reset the homeostatic Ca2+ levels in prostate cancer cells, leading to different responses and sensitivities to bicalutamide depending on the androgen and vitamin D status of the patients. (Supported by NCI RO1-CA101114). Citation Information: Cancer Res 2009;69(23 Suppl):A48.
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