Elevated serum uric acid (SUA) or urate, causing gout, has being linked to cancers, especially prostate cancer (PCa) (1). Activins, inflammatory cytokines of the TGFβ superfamily, act as negative growth regulators in the prostate, and activin insensitivity is considered a hallmark of PCa progression. However, the underlying molecular mechanisms of activin insensitivity and ‘cellular uric acid homeostasis’ (CUAH) in PCa are unknown. This study aimed to determine how a disturbance of CUAH counteracts growth inhibitory effects of activins in PCa, and to identify the transporter facilitating this. Expression of activin A and B (ActA, ActB), urate transporter GLUT9 and tissue urate levels were examined in arrays of human prostate disease via immunohistochemistry. Intracellular and secreted urate levels and GLUT9 mRNA and protein expression were determined in human PCa cell-lines LNCaP, DU145 and PC3. Additionally, effects of extracellular urate (200, 300 and 500µM) combined with ActA or ActB or probenecid, a urate transport inhibitor, and knock-down of GLUT9 (GLUT9-kd) were tested on LNCaP cell growth. Finally, [14C]-urate transport studies were conducted on LNCaP cells using probenecid. ActA expression was increased in low-grade PCa (normal: 5.6 ± 1.1 vs GS4-5: 9.0 ± 1.8, n=11-12, p<0.05), whereas ActB expression was reduced in high-grade (normal: 5.9 ± 1.1 vs GS4-5: 3.9 ± 1.6, n=20 and 11, p<0.05) and extra-capsular spread (5.9 ± 1.1 vs 3.2 ± 1.4, n=20 and 24, p<0.05) PCa. Intracellular urate levels decreased in all prostate pathologies, while expression of GLUT9 decreased in benign prostatic hyperplasia (BPH, normal: 7.6 ± 0.9 vs BPH: 2.9 ± 0.9, n=12 and 26, p<0.05), prostatitis (7.6 ± 0.9 vs 3.0 ± 0.7, n=12 and 9, p<0.05) and high-grade PCa (7.6 ± 0.9 vs 5.4 ± 0.7, n=12 and 20, p<0.05, Mann-Whitney U test). Activin responsive LNCaP cells had higher intracellular (90.1% ± 9.7 vs 32.53 % ± 12.53) and lower secreted (9.9% ± 9.7 vs 67.47 % ± 12.53, n=3, p<0.05, ANOVA) urate levels than activin insensitive PC3 cells. LNCaP and DU145 cells showed a decrease of GLUT9 mRNA consistent with prostate disease tissue and PCa cell protein expression. Normal and high extracellular urate (300 and 500µM) was growth promoting in vitro (122% and 165%, n=3-5, p<0.05, ANOVA), and it antagonised the growth inhibitory effects of ActA and ActB. This was abolished by the gout medication probenecid and reduced by a GLUT9-kd (100% ± 12.5 vs 84% ± 16.6, n=3, p<0.05, ANOVA). [14C]-urate transport in LNCaP cells was inhibited by probenecid (40%, n=3, p<0.0001, t-test) and matched by a similar inhibition of LNCaP cell proliferation under high extracellular urate. Implications: Changes of CUAH facilitated by GLUT9 significantly impact prostate cancer cell growth, and lowering SUA levels in PCa could be of therapeutic benefit (2).