The therapeutic value of SC66 in human renal cell carcinoma cells
The therapeutic value of SC66 in human renal cell carcinoma cells
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SC66对人肾细胞癌细胞的治疗价值。
DOI：
10.1038/s41419-020-2566-1
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发表时间：
2020-05-11
影响因子：
9
通讯作者：
Zhu, Jin
中科院分区：
文献类型：
--
作者：
Xu, Ming;Wang, Yin;Zhu, Jin
PI 3 K-AKT-mTOR级联是肾细胞癌（RCC）进展所需的。SC 66是一种新型AKT抑制剂。我们发现SC 66抑制RCC细胞系（786-O和A498）和患者来源的原代RCC细胞的活力、增殖、迁移和侵袭。尽管SC 66阻断了RCC细胞中AKT-mTORC 1/2的激活，但它在AKT抑制/沉默的RCC细胞中仍具有细胞毒性。在RCC细胞中，SC 66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激活而发生，而不依赖于AKT抑制。ROS清除剂N-乙酰半胱氨酸，JNK抑制剂（JNKi）和抗神经酰胺鞘脂鞘氨醇-1-磷酸都减弱了786-O细胞中SC 66诱导的细胞毒性。在体内，口服SC 66可有效抑制SCID小鼠皮下786-O异种移植物生长。在SC 66处理的786-O异种移植肿瘤中检测到AKT-mTOR抑制、SphK 1抑制、神经酰胺积累和JNK激活，表明SC 66通过AKT依赖性和AKT非依赖性机制抑制RCC细胞进展。
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.