Clinical significance of steroid and xenobiotic receptor and its targeted gene CYP3A4 in human prostate cancer,

The steroid and xenobiotic receptor (SXR) regulates cytochromeP450 (CYP) enzymes, which are key inactivators of testosterone inthe liver and prostate. In the present study, we investigated SXRexpression in human prostate tissues. We determined SXR immunoreactivityusing an anti-SXR antibody in benign (n = 78) andcancerous (n = 106) tissues obtained by radical prostatectomy.Stained slides were evaluated for the proportion and stainingintensity of immunoreactive cells. Total immunoreactivity (IR)scores (range: 0–8) were calculated as the sum of the proportionand intensity scores. Associations between the clinicopathologicalfeatures of the patients, SXR status, and CYP3A4 immunoreactivitywere analyzed. Western blot analyses validated the specificity ofthe anti-SXR antibody in 293T cells transfected with pcDNA–FLAG–SXR. Positive (IR score: ‡ 2) nuclear SXR staining was observed in91% (71 ⁄ 78) of benign foci and 47% (50 ⁄ 106) of cancerous lesions.Immunoreactivity scores were significantly lower in the cancerouslesions than in the benign foci (P < 0.0001). Clinicopathologicalanalyses showed that cancer-specific survival in patients with highSXR IR scores (‡4) was significantly increased (P = 0.046). Combineddata of present and previous studies showed that high IRscores for both the SXR and CYP3A4 correlated with significantlybetter cancer-specific survival rates in multivariate regression analyses(hazard ratio: 2.15, 95% confidence interval: 1.25–3.55,P = 0.007). We showed differential SXR expression in human prostatetissues. The high expression of the SXR and CYP3A4 is astrong prognostic indicator of favorable outcomes in prostatecancer, and could be a therapeutic target. (Cancer Sci 2012; 103:176–180)Endocrine therapies for advanced or recurrent prostate cancer(PC) are intended to decrease levels of circulatingandrogens and ⁄ or reduce androgen receptor (AR) activity.(1)Unfortunately, PC frequently develops into castration-resistantprostate cancer (CRPC). In CRPC, AR activity is often preservedby various mechanisms, including changes in intratumorligand concentration, AR gene amplification, AR mutations,changes in regulatory molecules, and ligand-independent ARactivation through kinase cross-talk.(2) Additionally, CRPCresults in high androstenediol levels in PC tissues, even afterandrogen-deprivation therapy.(3) Androstenediol is a morepotent activator of the mutant AR than dihydrotestosterone(DHT) in LNCaP cells, and induces greater cell proliferation.(3)Moreover, cells of a hormone-refractory MDA–PCa-2b subline,which is a metastasis-derived subline generated in vitro frombone, are stimulated by low levels of testosterone.(4) We alsoproposed a possible correlation between PC and intraprostaticandrogen metabolism.(5) In our previous study, decreased cytochromeP450 (CYP)2B6 expression contributed to the progressionof human PC, and transfection of the CYP2B6 geneinhibited proliferation of LNCaP cells.(5) Dihydrotestosterone isinactivated by the enzyme CYP3A4, which is a member of theCYP450 family and is responsible for the hydroxylation of testosteronein the liver and prostate.(6–11) In our previous study,decreased CYP3A4 expression was associated with a higherGleason score (GS) and significantly decreased cancer-specificsurvival in human PC.(12) Therefore, decreased CYP3A4 activitymight contribute to the increased bioavailability of intraprostaticDHT and the subsequent development of PC.Cytochrome P450 3A4 expression is regulated by the steroidand xenobiotic receptor (SXR), also known as the human pregnaneX receptor, which consists of members of the NR1I nuclearreceptor subfamily of ligand-activated transcription factors.(13,14)The SXR is expressed primarily in the liver, intestine, kidney,lung, stomach, peripheral blood monocytes, blood–brain barrier,uterus, ovary, placenta, breast, osteoclasts, heart, adrenal gland,bone marrow, and specific regions of the brain.(13) This wideexpression pattern indicates that the SXR is part of a protectivemechanism for critical cells that are sensitive to aberrant levels ofexogenous or endogenous compounds, such as phenobarbital,dexamethasone (DXM), prednisolone (PSL), androstane, andestrogens.(13) Recent studies have also revealed SXR-activated,signal-regulated proliferation in breast and colon cancer.(15,16)Therefore, we hypothesized that the SXR, which is upstream ofthe CYP3A4 gene, might be associated with PC progression. Inthe present study, we investigated the SXR expression in humanprostate tissues using an anti-SXR antibody.