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GNAS1 encodes the a-subunit of the Gs protein (Gsa), which binds GTP and stimulates adenylyl cyclase. Activating mutations lead to somatotroph, thyroid, adrenal and gonadal adenomas or the McCune-Albright syndrome and recently the T399C polymorphism in GNAS1 has been reported to be associated with malignancies. The purpose of the present case-control study with 349 Japanese prostate cancer patients and 203 urological controls was to determine whether the GNAS1 T393C polymorphism is associated with prostate cancer risk.The GNAS1 T393C polymorphism was examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Odds ratios (OR) were adjusted for age using multiple logistic regression analysis with SPSS Medical Pack.The allele frequencies were compatible with the control population in Hardy-Weinberg equilibrium with 80, 169 and 100 for GNAS1 C/C, C/T and T/T, respectively in the patients with prostate cancer, compared with 42, 94 and 67 in the controls. No association between the GNAS1 polymorphism and prostate cancer risk was apparent. The C/C genotype was more frequent among the prostate cancer patients (22.9%) than the controls (20.7%), although without significance (OR, 1.30; 95% CI, 0.80-2.12; p=0.29).This pilot study does not support involvement of the GNAS1 polymorphism in prostate cancer risk.

Prostate-specific antigen (PSA) gene expression is regulated by androgen receptor (AR) through androgen response elements (AREs) in the promoter region of the PSA gene. A single nucleotide polymorphism with guanine (G) to adenine (A) substitution is identified at position -158 in the ARE of the PSA gene. The purpose of this study was to investigate the allelic differences in the PSA promoter activity in vitro and the relation to several clinical factors of prostate cancer patients in the Japanese population. No significant differences of promoter activity in luciferase assay and binding activity of androgen receptor were noted between the two alleles in vitro. The PSA -158 G/A polymorphism was determined by PCR amplification and restriction digestion assays in 101 organ-confined prostate cancer (PC) patients who underwent radical prostatectomy and 52 controls with benign prostatic hyperplasia. The results revealed that homozygosity for the A allele in Japanese is less common (only 8.5%) than in ethnic populations. There were no significant differences in serum PSA value at the time of diagnosis, differentiation of cancer, pathological stage, cancer volume or ratio of serum PSA/ cancer volume. However, cancer volume after neoadjuvant endocrine therapy was significantly smaller in GG genotype than in AA + AG genotypes. Our data indicate that the PSA -158 G/A polymorphism has no effect on the PSA promoter activity in vitro and no association with the serum PSA level in Japanese men, however suggest that the patients with GG genotype of ARE1 may be more sensitive to androgen ablation therapy. Taken together, the ARE1 polymorphism in the PSA gene promoter may be one of the biomarkers for response to androgen deprivation therapy.

We have demonstrated that phenylacetate (PA)induced cell cycle arrest in human prostate cancer is mediated by increase of p27. In this study, we further investigated the mechanism of PA-induced p27 expression in prostate cancer cells (LNCaP, androgen-independent LNCaP [AIDL] and PC-3). A striking decrease in Skp2 mRNA and protein expression and reciprocal increase in p27 protein level were observed in three PA-treated prostate cancer cells. Interestingly, reduction of phospho-Akt and up-regulation of p27 mRNA levels were observed only in PC-3 cells. No significant differences were found in phospho-Akt and p27 mRNA levels in LNCaP and AIDL. In vitro ubiquitination assay showed a decreased p27 ubquitination in PA-treated prostate cancer cells. Our results suggest that PA attenuated Skp2 expression, thereby inhibiting ubiquitination and promoting p27 accumulation in all three prostate cancer cell lines. Therapeutic strategies designed to reduce Skp2 may clinically play an important role in the treatment of both androgen-sensitive and hormone-refractory prostate cancer.

Carcinogenesis of the prostate involves androgen influences, and associations between genetic polymorphisms of androgen receptor and metabolizing enzymes and prostate cancer risk have been reported. Roles for non-androgenic hormones are not well defined, but they also may have an impact judging from epidemiological and animal experimental alphalambda zeta of data. The purpose of the study was to determine whether hormone-related polymorphisms are associated with prostate cancer risk. A case-control study was performed with 147 Japanese prostate cancer patients and 266 urological controls. Polymorphisms of target genes [cytochrome P450 (CYP) 1B1, Leu432Val; debrisoquine hydroxylase, (CYP2D6)*4; aromatase (CYP19), Arg264Cys; estrogen receptor (ER)alpha-Xx (Xba I) and Pp (Pvu II); ERbeta-Rr (Rsa I); progesterone receptor (PR) Alu in intron 7] were examined by PCR-based methods. The capital and small letters signify the absence and presence of restriction sites, respectively. Odds ratios (OR) were adjusted for age using multiple logistic regression analysis with SPSS Medical Pack. Among the seven examined genetic polymorphisms, significant associations between CYP1B1 Leu432Val (OR 4.80; 95% confidence interval (CI), 1.21-19.05) and Alu in intron 7 of PR (OR 4.17; 95%CI, 1.26-13.85) were found. As for combined effects, the CYP1B1 polymorphisms (Leu/Val+Val/Val) together with heterozygosity for Alu in the PR were more frequent among prostate cancer patients (1.45%) than controls (0.41%), although without significance (OR, 3.99; 95%CI, 0.36-44.8). The combination of ERalpha (P/p+p/p) polymorphisms with heterozygosity for Alu in the PR demonstrated an OR of 4.56 (95%CI, 1.01-20.6). This pilot study showed that CYP1B1 and PR polymorphisms, alone or in combination, might be associated with prostate cancer risk. They might, therefore, have potential as a tool for identifying high-risk individuals.

Phenylacetate (PA), an aromatic fatty acid, is now undergoing evaluation as a potential anticancer reagent. Our previous study showed that PA induces cell growth inhibition in prostate cancer cells. Here, we investigated whether PA is effective against three renal cancer cell lines in vitro.The cell viability of PA-treated renal carcinoma cell lines (Caki-1, Os-RC-2 and RCC10) was assessed by trypan-blue exclusion and cell cycle distribution by flow cytometry. The cell cycle-regulatory protein expression was evaluated by Western blot, immunoprecipitation and kinase assay.Growth inhibition occurred with PA treatment at a dose of 2-5 mM and an increased percentage of cells in G1 after 24 hours of exposure. Reduced phosphorylation of the retinoblastoma protein (Rb) and CDK2 activity, increased expression of p21Cip1 and enhanced binding of p21Cip1 to CDK2 were observed following treatment with PA.Overall, these results suggest that p21Cip1 is a critical target in PA-mediated cell growth inhibition in RCC cells playing a key role in CDK2 inactivation, hypophosphorylation of pRb and subsequent G1 cell cycle arrest.