# Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo

## TL;DR

A new drug called ABC294640 inhibits colorectal cancer growth in lab and animal studies by targeting a specific enzyme.

## Contribution

ABC294640 is a novel SphK2 inhibitor that effectively inhibits CRC cell growth both in vitro and in vivo.

## Key findings

- ABC294640 inhibits SphK activity, reduces S1P levels, and increases ceramide in CRC cells.
- ABC294640 activates JNK signaling and inhibits AKT-S6K1 in CRC cells.
- ABC294640 oral administration inhibits CRC tumor growth in mice.

## Abstract

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.