The sphingosine kinase inhibitor 2-(p-hyroxyanilino)-4-(p-chlorophenyl)thiazole reduces androgen receptor expression via an oxidative stress-dependent mechanism

Tonelli, F. and Alossaimi, M. and Williamson, L. and Tate, R.J. and Watson, D.G. and Chan, E. and Bittman, R. and Pyne, N.J. and Pyne, S. (2013) The sphingosine kinase inhibitor 2-(p-hyroxyanilino)-4-(p-chlorophenyl)thiazole reduces androgen receptor expression via an oxidative stress-dependent mechanism. British Journal of Pharmacology, 168 (6). pp. 1497-1505. ISSN 1476-5381

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Abstract

Sphingosine kinase catalyses the formation of sphingosine 1-phosphate and is linked with androgen receptor signaling in prostate cancer cells. Therefore, we investigated the effect of sphingosine kinase inhibitors on androgen receptor expression. Androgen-sensitive LNCaP cells were treated with SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole), which inhibits sphingosine kinases 1 and 2 activity, and the effect on androgen receptor expression was measured. Treatment of cells with SK1 inhibitors reduced the expression of the androgen receptor and prostatic specific antigen, while (R)-FTY720 methyl ether (a sphingosine kinase 2 specific inhibitor) at a concentration that eliminates sphingosine kinase 2 from cells had no significant effect on androgen receptor expression. The effect of SKi on androgen receptor expression was independent of the SKi-induced proteasomal degradation of SK1 and was post-translational, although androgen receptor mRNA transcript was reduced. Fumonisin B1 (a ceramide synthase inhibitor) also failed to reverse the effect of SKi on androgen receptor expression, thereby excluding a role for ceramide derived from the salvage pathway. The effect of SKi on androgen receptor expression was reversed by N-acetylcysteine, which was used to scavenge reactive oxygen species. Inhibition of sphingosine kinase 1 activity abrogates androgen receptor signaling via an oxidative stress-induced, p53-independent mechanism in prostate cancer cells. Therefore, SK1 inhibitors may offer therapeutic potential in promoting the removal of the AR receptor from prostate cancer cells, resulting in an increased efficacy which is likely to be superior to inhibitors that simply reversibly inhibiting AR signaling.