期刊
AGING-US
卷 12, 期 19, 页码 19147-19158出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.103723
关键词
renal cell carcinoma; PI3K/AKT/mTOR; VS-5584; BRD4; chemosensitization
资金
- National Natural Science Foundation of China [81773221]
- Natural Science Foundation of Jiangsu Province [BK20161222, BK20191170]
- Suzhou Science and Technology Planed Projects [SS201857, SYS2018010, SYS2018062]
- Key Young Talents of Medicine in Jiangsu [QNRC2016875]
- Suzhou key clinical diseases diagnosis and treatment technology special project [LCZX201930]
- Suzhou Hightech Zone Medical and Health Technology Plan Project [2017Z005]
- Pre Research Fund Project of The Second Affiliated Hospital of Soochow University [SDFEYBS1707]
- Suzhou Program for Promoting health through science and education [KJXW2017069]
- Kunshan Natural Science Foundation [KS1714]
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.
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