|dc.description.abstract||Elevated extracellular uric acid is associated with inflammation and gout. Activins are inflammatory cytokines and negative growth regulators in the prostate. Both uric acid and activins are elevated in the synovial fluid of patients with gout. Recent evidence has linked elevated uric acid and cancers but little is known about uric acid in prostate cancer. A hallmark of prostate cancer progression is activin insensitivity and the mechanisms underlying the inability to respond to activins are unclear.
It is proposed that elevated uric acid is evident during prostate cancer progression and this is one of the local factors that blocks the growth inhibitory effects of activin
To test our hypothesis, we examined the expression of activins A & B, uric acid and the urate transporter, GLUT9, in human prostate disease tissue arrays. Intracellular and secreted uric acid in human prostate cancer cell lines was also assessed. The effect of uric acid in the presence of activin was assessed in the activin responsive LNCaP prostate cancer cell line as was TGF-β mediated gene expression. Finally, the effect of probenecid, which inhibits the reabsorption of urate, was assessed in an activin responsive and activin insensitive prostate cancer cell line.
Results show uric acid expression significantly decreased in all prostate diseases, including BPH and prostate cancer. No differences were evident for activin A but activin B expression reduced in both BPH and prostate cancer. Human prostate cancer cell-lines showed striking differences in intracellular and secreted uric acid. The activin responsive LNCaP cell-line had higher intracellular uric acid and lower secreted uric acid than the activin insensitive PC3 cell-line. Uric acid caused a dose-dependent growth promotion on LNCaP cells, and antagonised the growth inhibitory effect of activin A & B. Through TGF-β arrays, it was evident that this growth promotion was not due to alterations in TGF-β superfamily signalling. Exposure of a known gout treatment, probenecid (1 mM), was unable to restore activin sensitivity in the PC3 cell line. Overall, this thesis demonstrates for the first time that elevated extracellular uric acid is growth promoting in vitro, increased uric acid antagonises the growth inhibitory effects of activins independent to canonical activin signalling and Probenecid was growth inhibitory in the LNCaP cell line.
These results indicate lowering extra-cellular uric acid and targeting uric acid transport may be beneficial in prostate cancer.||