The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth.
The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth.
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DOI：
10.7150/ijbs.71381
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发表时间：
2022
影响因子：
9.2
通讯作者：
Cai, Shang
中科院分区：
文献类型：
--
作者：
Zhang, Yan;Cheng, Long;Shi, Xin;Song, Yu;Chen, Xiao-yu;Chen, Min-bin;Yao, Jin;Zhang, Zhi-qing;Cai, Shang
鞘氨醇激酶 1/2 (SphK1/2) 的过度表达和/或过度激活对于宫颈癌的肿瘤发生和进展很重要。目前的研究检查了 SKI-V（一种非脂质小分子 SphK 抑制剂）对抗宫颈癌细胞的潜在活性和信号传导机制。在不同的原代和永生化宫颈癌细胞中，SKI-V 通过抑制细胞活力、集落形成、增殖、细胞周期进程和细胞迁移发挥显着的抗癌活性。在 SKI-V 处理的宫颈癌细胞中检测到显着的细胞凋亡激活。值得注意的是，SKI-V 还在宫颈癌细胞中引发程序性坏死级联，因为它诱导线粒体 p53-亲环蛋白-D-腺嘌呤核苷酸易位子-1 (ANT1) 络合、线粒体膜电位崩溃、活性氧产生以及乳酸脱氢酶释放到培养基中。此外，SKI-V 阻断 SphK 激活并诱导原发性宫颈癌细胞中的神经酰胺积累，而不影响 SphK1/2 表达。 SKI-V 在宫颈癌细胞中诱导的细胞毒性在很大程度上被 1-磷酸鞘氨醇或 SphK1 激活剂 K6PC-5 抑制，但通过添加短链神经酰胺 C6 可以使其敏化。此外，SKI-V 抑制原发性宫颈癌细胞中 Akt-mTOR（雷帕霉素的哺乳动物靶标）的激活，并且其细胞毒性被组成型活性 Akt 减轻。在体内，每日腹腔注射SKI-V可显着抑制裸鼠皮下原发性宫颈癌异种移植物的生长。 SphK 抑制剂 SKI-V 在体外和体内共同抑制宫颈癌的生长。
Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical cancer cells. In different primary and immortalized cervical cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant apoptosis activation was detected in SKI-V-treated cervical cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, reactive oxygen species production and the release of lactate dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt. In vivo, daily intraperitoneal injection of SKI-V significantly inhibited subcutaneous primary cervical cancer xenograft growth in nude mice. Together, the SphK inhibitor SKI-V suppresses cervical cancer growth in vitro and in vivo.
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