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Sphingosine kinase 1 and 2 (SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. Alterations in SK1 function have been implicated in human prostate cancer, being involved in the acquisition of therapy resistance and progression to androgen independence, two major issues in the clinical management of this disease. This study investigated the effect of down-regulating SK1 in androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI) prostate cancer cells. The SK1 inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi) activates the proteasome by acutely inhibiting SK1 activity. Consequently, SKi induces the proteasomal degradation of SK1 isoforms, SK1a and SK1b, in LNCaP cells, which is associated with the accumulation of the pro-apoptotic lipid C22:0 ceramide and the induction of apoptosis. In contrast, SK1b is resistant to SKi-induced proteasomal degradation in LNCaP-AI cells, and this is associated with the failure to elevate ceramide le vels and to induce apoptosis. However, a different SK1 inhibitor, (S)-FTY720 vinylphosphonate overcomes this resistance to induce the proteasomal degradation of both SK1a and SK1b in LNCaP-AI cells, resulting in C16:0 ceramide accumulation and activation of apoptosis. The analysis of the effects of a selective inhibitor of SK2 revealed that SK1 and SK2 might regulate distinct functional pools of sphingolipids in prostate cancer cells. Additionally, SK1 inhibitors markedly reduce androgen receptor (AR) expression in prostate cancer cells. In particular, SKi down-regulates AR via a reactive oxygen species-dependent mechanism. Indeed, SKi treatment induces a pronounced oxidative stress response in LNCaP and LNCaP-AI cells. Thus, this study highlights a significant role of SK1 in promoting androgen receptor-dependent signalling and maintaining the survival of prostate cancer cells. This study also provides the first documented evidence of increased stability of SK1b compared with SK1a, which is associated with resistance to apoptosis. Taken together, these findings provide useful information regarding SK1-targeted therapeutic intervention for the treatment of (prostate) cancer.