title: Prostaglandin 15d-PGJ(2) inhibits androgen receptor signaling in prostate cancer cells.
abstract: Androgen signaling, in particular overexpression of the androgen receptor (AR), is critical for the growth and progression of prostate cancer. Because the AR is amenable to targeting by small-molecule inhibitors, it remains the major druggable target for the advanced disease. Inflammation has also been implicated in the cancerous growth in the prostate. Here we show that 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), an endogenously produced antiinflammatory prostaglandin, targets the AR and acts as a potent AR inhibitor, rapidly repressing AR target genes, such as FKBP51 and TMPRSS2 in prostate cancer cells. However, exposure of prostate cancer cells to 15d-PGJ(2) does not simply evoke a general inhibition of nuclear receptor activity or transcription because under the same conditions, peroxisome proliferator-activated receptor-γ is activated by 15d-PGJ(2). Moreover, 15d-PGJ(2) rapidly triggers modifications of AR by small ubiquitin-related modifier-2/3 (SUMO-2/3), which may modulate the repressing effect of 15d-PGJ(2) on AR-dependent transcription. Chromatin immunoprecipitation assays indicate that the inhibitory effect of 15d-PGJ(2) on FKBP51 and TMPRSS2 expression occurs in parallel with the inhibition of the AR binding to the regulatory regions of these genes. However, the DNA-binding activity is not the only AR function targeted by 15d-PGJ(2) because the prostaglandin also blunted the androgen-dependent interaction between the AR amino and carboxy termini. In conclusion, our results identify 15d-PGJ(2) as a potent and direct inhibitor of androgen signaling, suggesting novel possibilities in restricting the AR activity in prostate cancer cells.
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Kaikkonen
authors.forename: Ville
authors.initials: V
authors.lastname: Paakinaho
authors.forename: Päivi
authors.initials: P
authors.lastname: Sutinen
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: Palvimo
mesh_terms: D059002:Androgen Receptor Antagonists; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014452:Ubiquitins / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D059002:Androgen Receptor Antagonists; D047495:PPAR gamma; D015230:Prostaglandin D2; D011944:Receptors, Androgen; D012697:Serine Endopeptidases; D025841:Small Ubiquitin-Related Modifier Proteins; D022021:Tacrolimus Binding Proteins; D014157:Transcription Factors; D014452:Ubiquitins; D000099159:Tacrolimus Binding Protein 5; C477819:15-deoxyprostaglandin J2; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; C421305:TMPRSS2 protein, human