1{alpha},25-Dihydroxyvitamin D3 inhibits growth of VCaP prostate cancer cells despite inducing the growth-promoting TMPRSS2:ERG gene fusion.
Vitamin D receptor (VDR) agonists have been shown to reduce the growth of several prostate cancer cell lines. However, the effects of VDR activation have not been examined in the presence of the recently identified androgen-regulated TMPRSS2:ERG gene fusions, which occur in a high percentage of prostate cancers and play a role in growth and invasiveness. In a previous microarray study, we found that VDR activation induces TMPRSS2 expression in LNCaP prostate cancer cells. Here we show that the natural VDR agonist 1alpha,25-dihydroxyvitamin D(3) and its synthetic analog EB1089 increase expression of TMPRSS2:ERG mRNA in VCaP prostate cancer cells; this results in increased ETS-related gene (ERG) protein expression and ERG activity as demonstrated by an increase in the ERG target gene CACNA1D. In VCaP cells, we were not able to prevent EB1089-mediated TMPRSS2:ERG induction with an androgen receptor antagonist, Casodex, although in LNCaP cells, as reported for some other common androgen receptor and VDR target genes, Casodex reduces EB1089-mediated induction of TMPRSS2. However, despite inducing the fusion gene, VDR agonists reduce VCaP cell growth and expression of the ERG target gene c-Myc, a critical factor in VDR-mediated growth inhibition. Thus, the beneficial effects of VDR agonist treatment override some of the negative effects of ERG induction, although others remain to be tested.
Washington
Michele N
MN
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza BCM130, Houston, Texas 77030, USA.
Weigel
Nancy L
NL
D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D015153:Blotting, Western; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002452:Cell Count; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D050596:Oncogene Fusion / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D014815:Vitamins / Q000494:pharmacology
D000726:Androgen Antagonists; D000813:Anilides; C072312:ERG protein, human; D009570:Nitriles; D015514:Oncogene Proteins, Fusion; D011944:Receptors, Androgen; D018167:Receptors, Calcitriol; C515553:TMPRSS2-ERG fusion protein, human; D014105:Tosyl Compounds; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014815:Vitamins; C053541:bicalutamide; D002117:Calcitriol; C078903:seocalcitol