Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.
Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.
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DOI：
10.1186/s13046-015-0205-y
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发表时间：
2015-09-04
期刊：
影响因子：
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通讯作者：
Li-Wei W
中科院分区：
文献类型：
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作者：
Xun C;Chen MB;Qi L;Tie-Ning Z;Peng X;Ning L;Zhi-Xiao C;Li-Wei W
结直肠癌（CRC）是中国乃至世界范围内的重大健康问题。它是癌症相关死亡的主要原因之一。因此，研究小组正在寻找新的和更有效的抗CRC药物。在这里，我们证明了ABC 294640，一种新的SphK 2抑制剂，诱导转化和原代CRC细胞的生长抑制和凋亡。ABC 294640可显著抑制结直肠癌细胞SphK活性，并伴有1-磷酸鞘氨醇（S1 P）耗竭和神经酰胺增加。外源性S1 P抑制ABC 294640诱导的HT-29细胞死亡。而C6神经酰胺和SphK 1抑制剂SKI-II促进了ABC 294640对HT-29细胞的细胞毒性。ABC 294640在转化和原代CRC细胞中抑制AKT-S6 K1，但激活JNK信号传导。JNK抑制剂（SP 600125和JNKi-II）减轻ABC 294640诱导的CRC细胞凋亡。此外，低浓度的ABC 294640在体外敏化5-FU和顺铂的活性。在体内，ABC 294640口服给药显著抑制HT-29异种移植物在裸鼠中的生长。通过ABC 294640靶向SphK 2在体外和体内都有效地抑制CRC细胞生长，ABC 294640可以被开发为用于治疗CRC的新型治疗剂。本文的在线版本（doi：10.1186/s13046-015-0205-y）包含补充材料，可供授权用户使用。
Colorectal cancer (CRC) is a major health problem in China and around the world. It is one of the leading causes of cancer-related deaths. Research groups are thus searching for novel and more efficient anti-CRC agents. Here we demonstrated that ABC294640, a novel SphK2 inhibitor, induced growth inhibition and apoptosis in transformed and primary CRC cells. The SphK activity was remarkably inhibited by ABC294640, accompanied by sphingosine-1-phosphate (S1P) depletion and ceramide incensement in CRC cells. Exogenously-added S1P inhibited ABC294640-induced HT-29 cell lethality. While C6 ceramide and SphK1 inhibitor SKI-II facilitated ABC294640-induced cytotoxicity against HT-29 cells. ABC294640 inhibited AKT-S6K1, but activated JNK signaling in transformed and primary CRC cells. JNK inhibitors (SP600125 and JNKi-II) alleviated ABC294640-induced CRC cell apoptosis. Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro. In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice. Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC. The online version of this article (doi:10.1186/s13046-015-0205-y) contains supplementary material, which is available to authorized users.