机构：[a]The Department of Urology, the Third Affiliated Hospital, Soochow University, Changzhou,[b]Institute of Neuroscience, Soochow University, Suzhou,[c]Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Suzhou,[d]The Department of Radiology, the Third Affiliated Hospital, Soochow University, Changzhou, China
Background/Aims: Mammalian target of rapamycin (mTOR) is a valuable treatment target of renal cell carcinoma (RCC). Palomid 529 is a novel mTORC1/2 dual inhibitor. Methods: RCC cells were treated with different concentrations of Palomid 529. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by BrdU ELISA assay. Cell apoptosis was tested by the Hoechst-33342 nuclei staining assay and Histone DNA ELISA assay. mTOR signaling was tested by Western blotting assay and co-immunoprecipitation (IP) assay. The SCID mouse 786-O xenograft model was established to test RCC cell growth in vivo. Results: Palomid 529 exerted cytotoxic, anti-proliferative and pro-apoptotic activities in 786-O RCC cells. Palomid 529 disassembled mTORC1/2, causing de-phosphorylation of mTORC1/2 substrates. Bromodomain-containing protein 4 (BRD4) is a primary resistant factor of Palomid 529. Palomid 529-induced 786-O cell apoptosis was sensitized by BRD4 inhibitors or BRD4 silencing, but inhibited with BRD4 over-expression. Palomid 529-induced cytotoxicity in the primary human RCC cells was negatively correlated with BRD4 expression level. In vivo, Palomid 529 i.p. administration inhibited 786-O xenograft tumor growth in SCID mice. Its anti-tumor activity was further sensitized by co-administration of the BRD4 inhibitor JQ1. Cconclusion: Palomid 529 inhibits RCC cell growth in vitro and in vivo. BRD4 inhibition could further sensitize Palomid 529 against RCC cells. (c) 2018 The Author(s) Published by S. Karger AG, Basel
基金：
This work was supported by the Natural Science Foundation of China (81371513 and
81401386).
第一作者机构：[a]The Department of Urology, the Third Affiliated Hospital, Soochow University, Changzhou,
通讯作者：
通讯机构：[*1]Department of Radiology, the Third Affiliated Hospital, Soochow University, Changzhou, 185 Ju-qian Street, Tian-ning District, Changzhou, Jiangsu 213003 (China)
推荐引用方式(GB/T 7714)：
Zhao-yu Xing,Yin Wang,Long Cheng,et al.Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo[J].CELLULAR PHYSIOLOGY AND BIOCHEMISTRY.2018,50(2):640-653.doi:10.1159/000494185.
APA：
Zhao-yu Xing,Yin Wang,Long Cheng,Jie Chen,Xiao-zhou He&Wei Xing.(2018).Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo.CELLULAR PHYSIOLOGY AND BIOCHEMISTRY,50,(2)
MLA：
Zhao-yu Xing,et al."Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo".CELLULAR PHYSIOLOGY AND BIOCHEMISTRY 50..2(2018):640-653
