title: The sphingosine kinase inhibitor 2-(p-hyroxyanilino)-4-(p-chlorophenyl)thiazole reduces androgen receptor expression via an oxidative stress-dependent mechanism.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cell Biology and Pharmaceutical Analysis and Metabolomics Groups, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tonelli
authors.forename: Manal
authors.initials: M
authors.lastname: Alossaimi
authors.forename: Leon
authors.initials: L
authors.lastname: Williamson
authors.forename: Rothwelle J
authors.initials: RJ
authors.lastname: Tate
authors.forename: David G
authors.initials: DG
authors.lastname: Watson
authors.forename: Edmond
authors.initials: E
authors.lastname: Chan
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000068876:Fingolimod Hydrochloride; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000068876:Fingolimod Hydrochloride; D016166:Free Radical Scavengers; D007527:Isoenzymes; D009363:Neoplasm Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D017430:Prostate-Specific Antigen; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013110:Sphingosine; D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C410798:AR protein, human