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Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo
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نویسنده
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xun c. ,chen m.-b. ,qi l. ,tie-ning z. ,peng x. ,ning l. ,zhi-xiao c. ,li-wei w.
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منبع
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journal of experimental and clinical cancer research - 2015 - دوره : 34 - شماره : 1
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چکیده
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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. © 2015 xun et al.
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کلیدواژه
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ABC294640; Ceramide and signaling; Colorectal cancer; Sphingosine kinase
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آدرس
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department of oncology,shanghai general hospital,shanghai jiaotong university,100 haining road,shanghai,hongkou district 200080,china,department of oncology,shanghai first people's hospital,nanjing medical university,shanghai, China, department of oncology,kunshan first people's hospital,jiangsu university,kunshan, China, department of oncology,shanghai general hospital,shanghai jiaotong university,100 haining road,shanghai,hongkou district 200080, China, department of oncology,shanghai general hospital,shanghai jiaotong university,100 haining road,shanghai,hongkou district 200080, China, department of oncology,shanghai general hospital,shanghai jiaotong university,100 haining road,shanghai,hongkou district 200080, China, department of oncology,shanghai general hospital,shanghai jiaotong university,100 haining road,shanghai,hongkou district 200080, China, department of oncology,shanghai general hospital,shanghai jiaotong university,100 haining road,shanghai,hongkou district 200080, China, department of oncology,shanghai general hospital,shanghai jiaotong university,100 haining road,shanghai,hongkou district 200080,china,department of oncology,shanghai first people's hospital,nanjing medical university,shanghai, China
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Authors
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