Format

Send to

Choose Destination
Br J Pharmacol. 2013 Mar;168(6):1497-505. doi: 10.1111/bph.12035.

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

Author information

1
Cell Biology and Pharmaceutical Analysis and Metabolomics Groups, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

Abstract

BACKGROUND AND PURPOSE:

Sphingosine kinase catalyses the formation of sphingosine 1-phosphate and is linked with androgen receptor signalling in prostate cancer cells. Therefore, we investigated the effect of sphingosine kinase inhibitors on androgen receptor expression.

EXPERIMENTAL APPROACH:

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.

KEY RESULTS:

Treatment of cells with SK1 inhibitors reduced the expression of the androgen receptor and prostate-specific antigen, while (R)-FTY720 methyl ether (a sphingosine-kinase-2-selective 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.

CONCLUSION AND IMPLICATIONS:

Inhibition of sphingosine kinase 1 activity abrogates androgen receptor signalling via an oxidative stress-induced, p53-independent mechanism in prostate cancer cells. Therefore, SK1 inhibitors may offer therapeutic potential in promoting the removal of AR receptors from prostate cancer cells, resulting in an increased efficacy, which is likely to be superior to inhibitors that simply reversibly inhibit AR signalling.

PMID:
23113536
PMCID:
PMC3596653
DOI:
10.1111/bph.12035
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center