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

Abstract

BackgroundColorectal 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.ResultsHere 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.ConclusionsTargeting 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0205-y) contains supplementary material, which is available to authorized users.

MicroRNA-613 inhibits cell growth, migration and invasion of papillary thyroid carcinoma by regulating SphK2

“…Increasing evidence suggests that alterations in SphK2 expression contribute to the pathogenesis of many human cancers [29–31]. SphK2 overexpression in bladder cancer cells is closely implicated in tumor progression.…”

“…Knockdown of SphK2 leads to decreased proliferation and enhanced chemosensitivity and apoptosis to gefitinib in non-small cell lung cancer [30]. The novel SphK2 inhibitor ABC294640 induces growth inhibition and apoptosis in transformed and primary colorectal cancer cells, suggesting that SphK2 may be involved in colorectal cancer development [31]. In this study, we found that SphK2 was a target gene of miR-613 and restoration of SphK2 expression abolished the inhibitory effect of miR-613 on cell proliferation and invasion.…”

Recent advances in the development of sphingosine kinase inhibitors

“…ABC294640 has been used extensively in vivo where it has shown some efficacy in animal models of solid tumours [50,98,113,114,116,118,124,125], blood cancers [36,37,121], and inflammatory conditions such as osteoarthritis [126], transplantation [120], stroke/ischemia [122,127] and colitis [128,129] (Table 2). It has been shown to dose-dependently decrease circulating S1P in mice [50] and S1P levels in xenograft tumours [50,112].…”

“…Despite the off-targets, ABC294640 was found to sensitise cancer cells to chemotherapy [50,[114][115][116][117][118], Bcl-2 inhibitors [37], the Bcr-Abl inhibitor Imatinib and the proteasome inhibitor Bortezomib [36]. ABC294640 was found to reduce pro-proliferative signalling through the Akt and MAPK pathways via reduction in S1P receptor signalling.…”

Targeting Sphingosine Kinases for the Treatment of Cancer

“…As summarized below, ABC294640 has therapeutic activity in diverse mouse tumor models both alone and in combination with other anticancer drugs (Antoon, White, Driver, Burow, & Beckman, 2012; Antoon et al, 2010; Antoon, White, et al, 2011; Beljanski et al, 2010; Beljanski, Knaak, et al, 2011; Beljanski, Lewis, et al, 2011; Dai et al, 2017; Dai, Smith, Foroozesh, Miele, & Qin, 2018; French et al, 2010; Qin et al, 2014; Schrecengost et al, 2015; Venant et al, 2015; Venkata et al, 2014; Wallington-Beddoe et al, 2014; Xu et al, 2018; Xun et al, 2015; Zhou, Chen, & Yu, 2018), as well as a number of rodent inflammation models (Fitzpatrick, Green, Frauenhoffer, et al, 2011; Fitzpatrick, Green, Maines, & Smith, 2011; Liu et al, 2012; Maines et al, 2008; Maines, Fitzpatrick, Green, Zhuang, & Smith, 2010; Maines et al, 2006; Poti et al, 2012; Shi et al, 2012) not discussed here. Additionally, ABC294640 diminished tumor incidence and multiplicity in the azoxymethane/dextran sulfate sodium model of colon carcinogenesis (Chumanevich et al, 2010).…”