1. BRD4 inhibition sensitizes renal cell carcinoma cells to the PI3K/mTOR dual inhibitor VS-5584
- Author
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Yuan-Yuan Liu, Jianbing Zhu, Yin Wang, Jin Zhu, Ming Xu, Lijun Xu, Guangcheng Dai, and Boxin Xue
- Subjects
Aging ,Programmed cell death ,renal cell carcinoma ,Cell growth ,Chemistry ,Cell Biology ,mTORC1 ,urologic and male genital diseases ,chemosensitization ,female genital diseases and pregnancy complications ,Downregulation and upregulation ,Apoptosis ,Cancer research ,PI3K/AKT/mTOR ,BRD4 ,Cytotoxicity ,VS-5584 ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Research Paper - Abstract
Activation of the PI3K/AKT/mTOR pathway promotes the progression of renal cell carcinoma (RCC). This study tested the anti-RCC cell activity of the PI3K/mTOR dual inhibitor, VS-5584. We show that VS-5584 inhibited PI3K/AKT/mTORC1/2 activation in established (786-O and A498 lines) and primary RCC cells, thereby suppressing cell survival, proliferation, migration and cell cycle progression. VS-5584 induced significant apoptosis in RCC cells. A daily single oral dose of VS-5584 (20 mg/kg) significantly inhibited 786-O tumor growth in vivo. VS-5584 treatment of 786-O tumor xenografts and RCC cells resulted in feedback upregulation of bromodomain-containing protein 4 (BRD4). Furthermore, BRD4 inhibition (by JQ1 and CPI203), knockdown or complete knockout potentiated VS-5584-induced RCC cell death and apoptosis. Conversely, forced overexpression of BRD4 attenuated the cytotoxicity of VS-5584 in 786-O cells. Collectively, VS-5584 potently inhibits RCC cell proliferation and survival. Its anti-tumor activity is further enhanced by the targeted inhibition of BRD4.
- Published
- 2020