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首页> 外文期刊>Cellular Physiology and Biochemistry >A novel mode of action of the putative sphingosine kinase inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI II): Induction of lysosomal sphingosine kinase 1 degradation
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A novel mode of action of the putative sphingosine kinase inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI II): Induction of lysosomal sphingosine kinase 1 degradation

机译：假定的鞘氨醇激酶抑制剂2-（对羟基苯胺基）-4-（对氯苯基）噻唑（SKI II）的新型作用方式：诱导溶酶体鞘氨醇激酶1降解

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Background: Sphingosine kinase 1 (SK1) is a key enzyme in the generation of sphingosine 1-phosphate (S1P) which critically regulates a variety of important cell responses such as proliferation and migration. Therefore, inhibition of SK-1 has been suggested to be an attractive approach to treat tumor growth and metastasis formation. Results: We show here that the previously developed putative SK-1 inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI II) displays an additional facet of action complementary to the known inhibition of enzymatic SK-1 activity. In various human cell lines including glomerular podocytes and mesangial cells, the human endothelial cell line EA.hy 926, and the lung cancer cell line NCI H358, SKI II reduced TGFβ-and TPA-stimulated cellular SK-1 activity by downregulating SK-1 protein expression without affecting SK-1 mRNA expression. By using cycloheximide to block the de novo protein synthesis, the protein expression of SK-1 under untreated conditions was stable over 24h. Under SKI II treatment, the half-live drastically decreased to approximately 0.8h. Mechanistically, this degradation occurred through a lysosomal pathway and involved cathepsin B since the general lysosomal inhibitor chloroquine and the specific cathepsin B inhibitor CA-074ME were able to reverse the effect of SKI II. Surprisingly, in vitro SK-1 activity assays revealed only a very weak direct inhibitory effect of SKI II on SK-1 overexpressed HEK293 cell lysates. Conclusion: These data show for the first time that the previously developed SK inhibitor SKI II hardly inhibits SK-1 directly but rather acts by triggering the lysosomal degradation of SK-1 in various cell types. This finding discloses a new mode of action of SKI II and strongly suggests that additional direct targets of SKI II may exist other than SK-1.
机译：背景：鞘氨醇激酶1（SK1）是鞘氨醇1-磷酸（S1P）产生中的关键酶，可严格调节各种重要的细胞反应，例如增殖和迁移。因此，已提出抑制SK-1是治疗肿瘤生长和转移形成的有吸引力的方法。结果：我们在这里显示先前开发的推定的SK-1抑制剂2-（对羟基苯胺基）-4-（对氯苯基）噻唑（SKI II）显示出另一种作用，与已知的酶SK-1抑制作用互补活动。在包括肾小球足细胞和肾小球系膜细胞在内的各种人类细胞系，人类内皮细胞系EA.hy 926和肺癌细胞系NCI H358中，SKI II通过下调SK-1降低TGFβ和TPA刺激的细胞SK-1活性。蛋白表达而不会影响SK-1 mRNA表达。通过使用环己酰亚胺阻断从头蛋白质的合成，未处理条件下SK-1的蛋白质表达在24小时内保持稳定。在SKI II处理下，半衰期急剧下降至约0.8h。从机理上讲，这种降解是通过溶酶体途径发生的，并涉及组织蛋白酶B，因为一般的溶酶体抑制剂氯喹和特定的组织蛋白酶B抑制剂CA-074ME能够逆转SKI II的作用。出人意料的是，体外SK-1活性测定揭示了SKI II对SK-1过表达的HEK293细胞裂解物的非常弱的直接抑制作用。结论：这些数据首次表明，先前开发的SK抑制剂SKI II几乎不能直接抑制SK-1，而是通过触发各种细胞类型中SK-1的溶酶体降解来起作用。这一发现揭示了SKI II的一种新的作用方式，并强烈暗示除了SK-1以外，还可能存在SKI II的其他直接靶标。

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