Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Institute of Neuroscience, Soochow University, Suzhou, China.
Cell Death Dis. 2020 May 11;11(5):353. doi: 10.1038/s41419-020-2566-1.
The PI3K-AKT-mTOR cascade is required for renal cell carcinoma (RCC) progression. SC66 is novel AKT inhibitor. We found that SC66 inhibited viability, proliferation, migration and invasion of RCC cell lines (786-O and A498) and patient-derived primary RCC cells. Although SC66blocked AKT-mTORC1/2 activation in RCC cells, it remained cytotoxic in AKT-inhibited/-silenced RCC cells. In RCC cells, SC66 cytotoxicity appears to occur via reactive oxygen species (ROS) production, sphingosine kinase 1inhibition, ceramide accumulation and JNK activation, independent of AKT inhibition. The ROS scavenger N-acetylcysteine, the JNK inhibitor (JNKi) and the anti-ceramide sphingolipid sphingosine-1-phosphate all attenuated SC66-induced cytotoxicity in 786-O cells. In vivo, oral administration of SC66 potently inhibited subcutaneous 786-O xenograft growth in SCID mice. AKT-mTOR inhibition, SphK1 inhibition, ceramide accumulation and JNK activation were detected in SC66-treated 786-O xenograft tumors, indicating that SC66 inhibits RCC cell progression through AKT-dependent and AKT-independent mechanisms.
PI3K-AKT-mTOR 级联反应是肾细胞癌 (RCC) 进展所必需的。SC66 是一种新型的 AKT 抑制剂。我们发现 SC66 抑制了 RCC 细胞系 (786-O 和 A498) 和源自患者的原发性 RCC 细胞的活力、增殖、迁移和侵袭。尽管 SC66 阻断了 RCC 细胞中的 AKT-mTORC1/2 激活，但在 AKT 抑制/沉默的 RCC 细胞中仍具有细胞毒性。在 RCC 细胞中，SC66 的细胞毒性似乎通过活性氧 (ROS) 产生、鞘氨醇激酶 1 抑制、神经酰胺积累和 JNK 激活来发生，而与 AKT 抑制无关。ROS 清除剂 N-乙酰半胱氨酸、JNK 抑制剂 (JNKi) 和抗神经酰胺鞘脂神经酰胺-1-磷酸均可减弱 786-O 细胞中 SC66 诱导的细胞毒性。在体内，SC66 的口服给药可有效抑制 SCID 小鼠皮下 786-O 异种移植物的生长。在 SC66 处理的 786-O 异种移植瘤中检测到 AKT-mTOR 抑制、SphK1 抑制、神经酰胺积累和 JNK 激活，表明 SC66 通过 AKT 依赖性和 AKT 非依赖性机制抑制 RCC 细胞的进展。
