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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Receptor Antagonists / chemistry
  • Androgen Receptor Antagonists / pharmacology
  • Antineoplastic Agents / antagonists & inhibitors
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Down-Regulation / drug effects*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fingolimod Hydrochloride
  • Free Radical Scavengers / pharmacology
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Male
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Oxidative Stress / drug effects*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Propylene Glycols / pharmacology
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Protein Processing, Post-Translational / drug effects
  • Protein Stability / drug effects
  • RNA, Messenger / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Thiazoles / antagonists & inhibitors
  • Thiazoles / pharmacology*


  • 4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol
  • AR protein, human
  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Isoenzymes
  • Neoplasm Proteins
  • Propylene Glycols
  • RNA, Messenger
  • Receptors, Androgen
  • Thiazoles
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Prostate-Specific Antigen
  • Fingolimod Hydrochloride
  • Sphingosine