鞘氨醇激酶（SphK）包括SphK1和SphK2是促进前列腺癌进展的重要酶。SKI-178是一种新型且高效的SphK1/2双重抑制剂。在这里，我们测试了SKI-178对前列腺癌细胞的潜在抗活性。生物信息学分析和局部组织的结果表明，人类前列腺癌组织中SphK1和SphK2均上调表达。通过慢病毒载体传导，SphK1和SphK2的异位过表达促进了原代前列腺癌细胞的增殖和迁移。在原代人类前列腺癌细胞和免疫细胞系中，SKI-178强烈抑制了细胞存活率、增殖、细胞周期进展和细胞迁移，导致细胞死亡和凋亡。SKI-178损害了线粒体功能，引起线粒体去极化、反应性氧化物产生和三磷酸腺苷耗竭。SKI-178有效抑制了前列腺癌细胞的SphK活性并诱导鞘烷类物质产生，而不影响前列腺癌细胞中的SphK1/2表达。此外，SKI-178抑制了前列腺癌细胞中的Akt-mTOR活化并诱导了JNK的活化。相反，一种构建激活型Akt1或药物类JNK抑制剂可以减轻SKI-178对前列腺癌细胞的细胞毒性作用。在体内，每日腹腔注射单剂量的SKI-178强烈抑制了裸鼠中PC-3异种移植物的生长。在应用SKI-178的PC-3异种移植物组织中检测到了SphK抑制、鞘烷类物质产生、三磷酸腺苷耗竭和脂质过氧化以及Akt-mTOR失活和JNK活化。总之，通过SKI-178靶向SphK1/2能够有效抑制前列腺癌细胞在体外和体内的生长。©2023年。作者（们）。

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.© 2023. The Author(s).