Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.
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.
Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. caixunshanghai2@163.com.|Department of Oncology, Shanghai First People's Hospital, Nanjing Medical University, Shanghai, China. caixunshanghai2@163.com.
Cai
C
Xun
Department of Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China. caocong1111@163.com.
Min-Bin
MB
Chen
Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. liqishjdmd@163.com.
Li
L
Qi
Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. drzhangtiening@163.com.
Zhang
Z
Tie-Ning
Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. xue_peng126@126.com.
Xue
X
Peng
Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. li_ningshjd6@yeah.net.
Li
L
Ning
Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. 8518608@qq.com.
Chen
C
Zhi-Xiao
Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. wangliwei1965@163.com.|Department of Oncology, Shanghai First People's Hospital, Nanjing Medical University, Shanghai, China. wangliwei1965@163.com.
Wang
W
Li-Wei
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
D000218:Adamantane; D000970:Antineoplastic Agents; D002945:Cisplatin; D005472:Fluorouracil; D017853:Phosphotransferases (Alcohol Group Acceptor); D011725:Pyridines; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide; C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase