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

Abstract

BACKGROUND AND PURPOSESphingosine 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 APPROACHAndrogen-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 RESULTSTreatment 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 IMPLICATIONSInhibition 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.

Transcriptome Analysis Reveals Crosstalk of Responsive Genes to Multiple Abiotic Stresses in Cotton (Gossypium hirsutum L.)

“…There were three putative thiamine biosynthesis proteins induced by the above stresses (Table 1), vitamin B1 (thiamine) is a player during plant adaptation to stresses, mainly oxidative stress [75,76]. Our results also showed that chlororespiratory reduction 3 (CRR3) [77], thiazole biosynthetic enzyme, the precursor of vitamin B1[78], G. hirsutum alcohol dehydrogenase 1 (ADH1) [79], PAP (Plastid-lipid associated protein) fibrillin, MAR-binding filament-like protein 1 (MFP1) [80], NDH-dependent cyclic electron flow 1, protein like Starch Excess 4 (SEX4) 1 [81], SAP domain-containing protein, phenylalanine ammonia-lyase 1 (PAL1) were commonly up-regulated.…”

The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo

“…The dual sphingosine kinase inhibitor SKI-II also diminishes AR expression independent of apoptotic or autophagy signaling (38). Since exogenous S1P was unable to restore AR expression, a role for intracellular S1P was implicated (38). Nuclear localization of both SPHK2 and the AR suggests the possibility that the SPHK2-derived pool of S1P could be important for its expression.…”

“…Nuclear localization of both SPHK2 and the AR suggests the possibility that the SPHK2-derived pool of S1P could be important for its expression. However, at 10 μM the SPHK2-specific inhibitor (R)-FTY720 methyl ether (ROME) failed to decrease AR expression and decreases at 50μM were thought to occur as a consequence of an off-target effect (38). Future studies using RNAi approaches will be needed to mechanistically investigate the relationship between sphingosine kinases and AR expression.…”

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

“…SKI II is a nonstructural analog of Des1 substrate and, as such, it does not probably directly interact with the Des1 protein. SKI II has been reported to induce oxidative stress ( 76 ), and so its activity as a Des1 inhibitor may result from its activity at modifying the redox status of cells. However, the occurrence of inhibition in cell lysates is against the involvement of reactive oxygen species.…”