Introduction: Visfatin/PBEF is a novel adipokine circulating inversely proportional to visceral fat mass and exerts insulin-mimetic effects; it is expressed in normal, inflamed and tumour tissues. Visfatin/PBEF has also been identified as NMPRTase, a key intracellular enzyme involved in NAD+ metabolism, replenishing NAD+ during cellular respiration. Inhibition of NMPRTase by the anti-cancer agent FK866 has been shown to induce apoptosis in tumours. Prostate cancer progression is associated with obesity and its metabolic sequelae, and we propose a role for visfatin/PBEF/NMPRTase in prostate carcinogenesis.
Materials and Methods: Visfatin expression was studied in normal and malignant prostate cancer tissue and LNCaP and PC3 human prostate cancer cell lines using RT-PCR, immunocytochemistry and confocal analysis. Regulation of visfatin expression by testosterone, 5-alpha dihydrotestosterone (DHT) (10−6M) interleukin-6 (30 ng/ml) and insulin-like growth factor-1 (IGF-1) (10 ng/ml) was studied using quantitative RT-PCR and Western blotting. We also investigated the effect of visfatin ± IGF-1 on LNCaP and PC3 cell proliferation.
Results: Visfatin mRNA and protein were detected in LNCaP and PC3 cells and normal and malignant prostate cancer tissue; visfatin protein demonstrated cytoplasmic and nuclear distribution. Testosterone, DHT and IGF-1 increased visfatin mRNA and/or protein expression in both the androgen-sensitive LNCaP and androgen-insensitive PC3 cell line. Treatment of PC3 cells with visfatin resulted in a dose-dependent increase in PC3 cell proliferation which was enhanced in the presence of IGF-1; co-incubation of visfatin and IGF-1 showed a synergistic dose-dependent increase cell proliferation in LNCaP cells.
Conclusions: Our novel findings demonstrate a multifunctional (intra- and extra-cellular) role for visfatin in prostate carcinogenesis, and provide greater insight into the molecular association between obesity and prostate cancer. High visfatin expression in prostate cancer cells may indicate poor prognosis, and inhibition of visfatin may represent a novel therapeutic target for treatment of this disease.
28 Apr - 02 May 2007
European Society of Endocrinology