Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth.
Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth.
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DOI：
10.1038/s41419-023-06023-4
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发表时间：
2023-08-21
影响因子：
9
通讯作者：
Tao, Wei
中科院分区：
文献类型：
--
作者：
Jin, Lu;Zhu, Jin;Yao, Linya;Shen, Gang;Xue, Bo-xin;Tao, Wei
鞘氨酸激酶（SphK），包括SphK1和SphK2，是促进前列腺癌进展的重要酶。SKI-178是一种新型高效SphK1/2双抑制剂。我们在此测试了SKI-178潜在的抗前列腺癌细胞活性。局部组织的生物信息学分析和结果表明，SphK1和SphK2在人前列腺癌组织中均上调。慢病毒构建的异位过表达SphK1和SphK2可促进原发性前列腺癌细胞的增殖和迁移。在原代人前列腺癌细胞和永生化细胞系中，SKI-178能有效抑制细胞活力、增殖、细胞周期进展和细胞迁移，导致细胞死亡和凋亡。SKI-178损伤线粒体功能，导致线粒体去极化、活性氧产生和ATP消耗。SKI-178有效抑制SphK活性，诱导神经酰胺产生，而不影响前列腺癌细胞中SphK1/2的表达。此外，SKI-178在前列腺癌细胞中抑制Akt-mTOR活化并诱导JNK活化。相反，组成活性Akt1构建物或药理学JNK抑制剂可减弱ski -178诱导的前列腺癌细胞的细胞毒性。在体内，每天腹腔注射单剂量的SKI-178能有效抑制裸鼠PC-3异种移植物的生长。在给予SKI-178的PC-3异种移植组织中检测到SphK抑制，神经酰胺产生，ATP消耗和脂质过氧化以及Akt-mTOR失活和JNK活化。总之，SKI-178靶向SphK1/2在体外和体内都能有效抑制前列腺癌细胞的生长。
Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo.
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影响因子：
8
作者：
Ezponda, T.;Popovic, R.;Shah, M. Y.;Martinez-Garcia, E.;Zheng, Y.;Min, D-J;Will, C.;Neri, A.;Kelleher, N. L.;Yu, J.;Licht, J. D.
通讯作者：
Licht, J. D.
影响因子：
7
作者：
Jin L;Zhang W;Yao MY;Tian Y;Xue BX;Tao W
通讯作者：
Tao W
DOI：
10.1124/jpet.114.219659
发表时间：
2015-03-01
影响因子：
3.5
作者：
Dick, Taryn E.;Hengst, Jeremy A.;Yun, Jong K.
通讯作者：
Yun, Jong K.
DOI：
10.1016/j.bbrc.2015.02.007
发表时间：
2015-03-13
影响因子：
3.1
作者：
Ji, Feng;Mao, Li;Fei, Haodong
通讯作者：
Fei, Haodong
影响因子：
2.7
作者：
Kumi-Diaka, J;Sanderson, NA;Hall, A
通讯作者：
Hall, A