Department of Thoracic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Gynecology and Obstetrics, The Second Affiliated Hospital Soochow University, Suzhou, China.
Cell Death Dis. 2022 Jul 12;13(7):602. doi: 10.1038/s41419-022-05049-4.
Sphingosine kinase 1 (SphK1) and sphingosine kinase (SphK2) are both important therapeutic targets of non-small cell lung cancer (NSCLC). SKI-349 is a novel, highly efficient and small molecular SphK1/2 dual inhibitor. Here in primary human NSCLC cells and immortalized cell lines, SKI-349 potently inhibited cell proliferation, cell cycle progression, migration and viability. The dual inhibitor induced mitochondrial depolarization and apoptosis activation in NSCLC cells, but it was non-cytotoxic to human lung epithelial cells. SKI-349 inhibited SphK activity and induced ceramide accumulation in primary NSCLC cells, without affecting SphK1/2 expression. SKI-349-induced NSCLC cell death was attenuated by sphingosine-1-phosphate and by the SphK activator K6PC-5, but was potentiated by the short-chain ceramide C6. Moreover, SKI-349 induced Akt-mTOR inactivation, JNK activation, and oxidative injury in primary NSCLC cells. In addition, SKI-349 decreased bromodomain-containing protein 4 (BRD4) expression and downregulated BRD4-dependent genes (Myc, cyclin D1 and Klf4) in primary NSCLC cells. At last, SKI-349 (10 mg/kg) administration inhibited NSCLC xenograft growth in nude mice. Akt-mTOR inhibition, JNK activation, oxidative injury and BRD4 downregulation were detected in SKI-349-treated NSCLC xenograft tissues. Taken together, targeting SphK1/2 by SKI-349 potently inhibits NSCLC cell growth in vitro and in vivo.
鞘氨醇激酶 1（SphK1）和鞘氨醇激酶 2（SphK2）都是非小细胞肺癌（NSCLC）的重要治疗靶点。SKI-349 是一种新型、高效的小分子 SphK1/2 双重抑制剂。在原代人 NSCLC 细胞和永生化细胞系中，SKI-349 能有效抑制细胞增殖、细胞周期进程、迁移和活力。双重抑制剂诱导 NSCLC 细胞线粒体去极化和凋亡激活，但对人肺上皮细胞无细胞毒性。SKI-349 抑制 SphK 活性并诱导原代 NSCLC 细胞中神经酰胺积累，而不影响 SphK1/2 的表达。SKI-349 诱导的 NSCLC 细胞死亡被 SphK 激活剂 K6PC-5 和 1-磷酸鞘氨醇减弱，但被短链神经酰胺 C6 增强。此外，SKI-349 在原代 NSCLC 细胞中诱导 Akt-mTOR 失活、JNK 激活和氧化损伤。此外，SKI-349 降低了原代 NSCLC 细胞中的溴结构域蛋白 4（BRD4）表达，并下调了 BRD4 依赖性基因（Myc、细胞周期蛋白 D1 和 Klf4）。最后，SKI-349（10mg/kg）给药抑制裸鼠 NSCLC 异种移植瘤的生长。在 SKI-349 处理的 NSCLC 异种移植组织中检测到 Akt-mTOR 抑制、JNK 激活、氧化损伤和 BRD4 下调。总之，SKI-349 通过靶向 SphK1/2 强烈抑制 NSCLC 细胞在体外和体内的生长。
