Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells.
Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells.
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DOI：
10.18632/oncotarget.7693
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发表时间：
2016-03-29
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影响因子：
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通讯作者：
Pyne S
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作者：
McNaughton M;Pitman M;Pitson SM;Pyne NJ;Pyne S
鞘氨醇激酶(SK1和SK2两种异构体)催化形成生物活性脂鞘氨醇1-磷酸。我们在这里证明了SK2抑制剂ABC294640(3-(4-氯苯基)金刚烷-1-羧酸(吡啶-4-甲基)酰胺)或SK1/SK2抑制剂SKI(2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole))诱导SK1a蛋白酶体降解(Mr=42 kDa)，并抑制雄激素非依赖性前列腺癌LNCaP-AI细胞的DNA合成。这些作用被二氢神经酰胺去饱和酶(DES1)抑制剂芬维甲素所概括。此外，SKI或ABC294640降低Jurkat细胞中Des1的活性，ABC294640诱导LNCaP-AI前列腺癌细胞中Des1(Mr=38 kDa)的蛋白酶体降解。此外，SKI或ABC294640或Fenretinide可增加LNCaP-AI前列腺癌细胞衰老标志物p53和p21的表达。SK1或SK2的siRNA敲除未能增加P53和p21的表达，但前者确实降低了LNCaP-AI前列腺癌细胞的DNA合成。此外，N-乙酰半胱氨酸(活性氧自由基清除剂)可阻断SK抑制剂诱导的p21和p53表达的增加，但对蛋白酶体的降解没有影响。此外，Des1的siRNA敲除增加了p53的表达，而Des1/SK1的siRNA组合则增加了p21的表达。因此，Des1和SK1参与调节LNCaP-AI前列腺癌细胞的生长，这涉及p53/p21依赖和不依赖的通路。因此，我们建议用影响Des1/SK1的化合物来靶向雄激素非依赖性前列腺癌细胞，以调节从头开始和神经鞘脂变阻器通路，以诱导生长停滞。
Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest.