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Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth
Cell Death & Disease ( IF 8.1 ) Pub Date : 2023-08-21 , DOI: 10.1038/s41419-023-06023-4
Lu Jin 1 , Jin Zhu 1 , Linya Yao 2 , Gang Shen 3 , Bo-Xin Xue 1 , Wei Tao 1
Affiliation  

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.



中文翻译:

SKI-178 靶向 SphK1/2 抑制前列腺癌细胞生长

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 是一种新型高效 SphK1/2 双重抑制剂。我们在此测试了 SKI-178 的潜在抗前列腺癌细胞活性。生物信息学分析和局部组织结果表明,SphK1 和 SphK2 在人前列腺癌组织中表达上调。慢病毒构建体异位过度表达 SphK1 和 SphK2,促进原发性前列腺癌细胞增殖和迁移。在原代人前列腺癌细胞和永生化细胞系中,SKI-178 有效抑制细胞活力、增殖、细胞周期进程和细胞迁移,导致细胞大量死亡和凋亡。SKI-178 损害线粒体功能,导致线粒体去极化、活性氧产生和 ATP 消耗。SKI-178 有效抑制 SphK 活性并诱导神经酰胺产生,而不影响前列腺癌细胞中 SphK1/2 的表达。此外,SKI-178 抑制前列腺癌细胞中的 Akt-mTOR 激活并诱导 JNK 激活。相反,组成型活性 Akt1 构建体或药理学 JNK 抑制剂减弱了 SKI-178 诱导的前列腺癌细胞细胞毒性。在体内,每日腹腔注射单剂量的 SKI-178 可有效抑制裸鼠体内 PC-3 异种移植物的生长。在施用 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 激活。总之,SKI-178 靶向 SphK1/2 可在体外和体内有效抑制前列腺癌细胞的生长。

更新日期:2023-08-21
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