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Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.
- Source :
- Journal of Experimental & Clinical Cancer Research (17569966); 9/4/2015, Vol. 34 Issue 1, p1-9, 9p
- Publication Year :
- 2015
-
Abstract
- Background: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 17569966
- Volume :
- 34
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Journal of Experimental & Clinical Cancer Research (17569966)
- Publication Type :
- Academic Journal
- Accession number :
- 109517910
- Full Text :
- https://doi.org/10.1186/s13046-015-0205-y