Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
Department of Hand and Foot Surgery, Hospital Affiliated 5 to Nantong University, Taizhou People’s Hospital, Taizhou, China.
Aging (Albany NY). 2020 Oct 27;12(20):20445-20456. doi: 10.18632/aging.103847.
CC-115 is a dual inhibitor of DNA-PKcs and mTOR, both are valuable therapeutic targets for renal cell carcinoma (RCC). Our results showed that CC-115 inhibited survival and proliferation of established RCC cell lines (786-O and A489) and primary human RCC cells. The dual inhibitor induced selective apoptosis activation in RCC cells, as compared to no cytotoxicity nor apoptotic effects toward normal renal epithelial cells. CC-115 inhibited DNA-PKcs and mTORC1/2 activation in RCC cells. It was however ineffective in DNA-PKcs-mTOR double knockout (DKO) 786-O cells. CC-115 induced feedback autophagy activation in RCC cells. Autophagy inhibitors or Beclin-1/Light chain 3 (LC3) silencing potentiated CC-115-induced anti-RCC cell activity. Conversely, ectopic overexpression of Beclin-1 inhibited CC-115-induced cytotoxicity. At last CC-115 oral administration inhibited 786-O subcutaneous xenograft growth in nude mice. Taken together, dual inhibition of DNA-PKcs and mTOR by CC-115 potently inhibited RCC cell growth.
CC-115 是 DNA-PKcs 和 mTOR 的双重抑制剂，两者都是肾细胞癌（RCC）的有价值的治疗靶点。我们的结果表明，CC-115 抑制了已建立的 RCC 细胞系（786-O 和 A489）和原代人 RCC 细胞的存活和增殖。与对正常肾上皮细胞无细胞毒性或凋亡作用相比，双重抑制剂在 RCC 细胞中诱导了选择性的凋亡激活。CC-115 抑制了 RCC 细胞中的 DNA-PKcs 和 mTORC1/2 激活。然而，它对 DNA-PKcs-mTOR 双敲除（DKO）786-O 细胞无效。CC-115 诱导了 RCC 细胞中的反馈自噬激活。自噬抑制剂或 Beclin-1/Light chain 3 (LC3) 沉默增强了 CC-115 诱导的抗 RCC 细胞活性。相反，外源性过表达 Beclin-1 抑制了 CC-115 诱导的细胞毒性。最后，CC-115 口服给药抑制了裸鼠皮下 786-O 异种移植的生长。总之，CC-115 对 DNA-PKcs 和 mTOR 的双重抑制强烈抑制了 RCC 细胞的生长。
