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The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells

机译：鞘氨醇激酶1和2在调节前列腺癌细胞中的Warburg效应中的作用

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Two isoforms of sphingosine kinase, SK1 and SK2, catalyze the formation of the bioactive lipid sphingosine 1-phosphate (S1P) in mammalian cells. We have previously shown that treatment of androgen-sensitive LNCaP prostate cancer cells with a non-selective SK isoform inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi), induces the proteasomal degradation of SK1. This is concomitant with a significant increase in C22:0-ceramide and sphingosine levels and a reduction in S1P levels, resulting in the apoptosis of LNCaP cells. In contrast, we show here that a SK2-selective inhibitor, (R)-FTY720 methyl ether (ROME), increases sphingosine and decreases S1P levels but has no effect on ceramide levels and does not induce apoptosis in LNCaP cells. We also show that several glycolytic metabolites and (R)-S-lactoylglutathione are increased upon treatment of LNCaP cells with SKi, which induces the proteasomal degradation of c-Myc. These changes reflect an indirect antagonism of the Warburg effect. LNCaP cells also respond to SKi by diverting glucose 6-phosphate into the pentose phosphate pathway to provide NADPH, which serves as an antioxidant to counter an oxidative stress response. SKi also promotes the formation of a novel pro-apoptotic molecule called diadenosine 5',5'''-P~1,P~3-triphosphate (Ap3A), which binds to the tumor suppressor fragile histidine triad protein (FHIT). In contrast, the SK2-selective inhibitor, ROME, induces a reduction in some glycolytic metabolites and does not affect oxidative stress. We conclude that SK1 functions to increase the stability of c-Myc and suppresses Ap3A formation, which might maintain the Warburg effect and cell survival, while SK2 exhibits a non-overlapping function.
机译：鞘氨醇激酶的两个同工型，SK1和SK2，在哺乳动物细胞中催化生物活性脂质鞘氨醇1-磷酸（S1P）的形成。我们以前已经表明，用非选择性SK同种型抑制剂2-（对羟基苯胺基）-4-（对氯苯基）噻唑（SKi）治疗雄激素敏感的LNCaP前列腺癌细胞会诱导SK1的蛋白酶体降解。这伴随着C22：0-神经酰胺和鞘氨醇水平的显着增加以及S1P水平的降低，从而导致LNCaP细胞凋亡。相反，我们在这里显示SK2选择性抑制剂（R）-FTY720甲基醚（ROME）增加鞘氨醇并降低S1P水平，但对神经酰胺水平没有影响，并且不诱导LNCaP细胞凋亡。我们还显示，在用SKi处理LNCaP细胞后，几种糖酵解代谢产物和（R）-S-乳糖基谷胱甘肽增加，这会诱导c-Myc的蛋白酶体降解。这些变化反映了Warburg效应的间接对抗。 LNCaP细胞还通过将6-磷酸葡萄糖转移到戊糖磷酸途径中来提供SKF应答，从而提供NADPH，NADPH可作为抗氧化剂来抵抗氧化应激反应。 SKi还促进形成新型的促凋亡分子，称为尿苷5'，5'''-P〜1，P〜3-三磷酸（Ap3A），其与肿瘤抑制因子脆弱的组氨酸三联体蛋白（FHIT）结合。相反，SK2选择性抑制剂ROME诱导某些糖酵解代谢产物减少，并且不影响氧化应激。我们得出的结论是，SK1的作用是增加c-Myc的稳定性并抑制Ap3A的形成，这可能维持Warburg效应和细胞存活，而SK2则表现出不重叠的功能。

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