ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer
ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer
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ABC294640 是一种鞘氨醇激酶 2 抑制剂，可增强 TRAIL 对非小细胞肺癌的抗肿瘤作用
DOI：
10.1080/15384047.2015.1056944
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发表时间：
2015-08-01
影响因子：
3.6
通讯作者：
Xie, Conghua
中科院分区：
文献类型：
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作者：
Yang, Jie;Yang, Chunxu;Xie, Conghua
有证据表明，肿瘤微环境可能在肿瘤耐药过程中发挥重要作用。鞘磷脂激酶2 （SphK2）被认为是鞘脂信号传导的关键调节因子。本研究旨在探讨SphK2特异性抑制剂（ABC294640）与肿瘤坏死因子相关凋亡诱导配体（TRAIL）联合应用分子靶向治疗是否能促进非小细胞肺癌（NSCLC）细胞的凋亡。我们的研究结果显示，NSCLC细胞对TRAIL的敏感性与SphK2的水平相关。与单独使用TRAIL相比，联合治疗可增强TRAIL诱导的细胞凋亡，并且siRNA敲低SphK2也有类似的效果。与ABC294640联合治疗可提高caspase-3/8活性，上调死亡受体（DR）表达。进一步的研究表明，添加ABC294640可以促进DR4/5向细胞膜表面的易位。然而，SphK2抑制剂对抗凋亡蛋白如Bcl-2和IAPs的表达没有显著影响。总之，本研究表明SphK2可能参与了NSCLC的凋亡抵抗，从而为耐药的NSCLC细胞提供了新的治疗靶点。
Evidences suggest that tumor microenvironment may play an important role in cancer drug resistance. Sphingosine kinase 2 (SphK2) is proposed to be the key regulator of sphingolipid signaling. This study is aimed to investigate whether the combination of molecular targeting therapy using a specific inhibitor of SphK2 (ABC294640), with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can enhance the apoptosis of non-small cell lung cancer (NSCLC) cells. Our results revealed that NSCLC cells' sensitivity to TRAIL is correlated with the level of SphK2. Compared with TRAIL alone, the combination therapy enhanced the apoptosis induced by TRAIL, and knockdown of SphK2 by siRNA presented a similar effect. Combination therapy with ABC294640 increased the activity of caspase-3/8 and up-regulated the expression of death receptors (DR). Additional investigations revealed that translocation of DR4/5 to the cell membrane surface was promoted by adding ABC294640. However, expression of anti-apoptosis proteins such as Bcl-2 and IAPs was not significantly modified by this SphK2 inhibitor. Overall, this work demonstrates that SphK2 may contribute to the apoptosis resistance in NSCLC, thus indicating a new therapeutic target for resistant NSCLC cells.