Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting beta 1 subunit expression and disrupting proteasome assembly

doi:10.1038/aps.2016.30

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	Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting beta 1 subunit expression and disrupting proteasome assembly
	Sun, Peng; Feng, Li-xing; Zhang, Dong-mei; Liu, Miao; Liu, Wang; Mi, Tian; Wu, Wan-ying; Jiang, Bao-hong; Yang, Min; Hu, Li-hong
刊名	ACTA PHARMACOLOGICA SINICA
	2016-07
卷号	37 期号:7 页码:908-918
关键词	bufalin ChanSu cardiac steroids proteasome beta 1 subunit proteasome assembly A549 human lung cancer cells proteomics
ISSN号	1671-4083
DOI	10.1038/aps.2016.30
文献子类	Article
英文摘要	Aim: Bufalin is one of the active components in the traditional Chinese medicine ChanSu that is used to treat arrhythmia, inflammation and cancer. BF211 is a bufalin derivative with stronger cytotoxic activity in cancer cells. The aim of this study was to identify the putative target proteins of BF211 and the signaling pathways in cancer cells. Methods: A549 human lung cancer cells were treated with BF211. A SILAC-based proteomic analysis was used to detect the protein expression profiles of BF211-treated A549 cells. Cellular proteasome activities were examined using fluorogenic peptide substrates, and the binding affinities of BF211 to recombinant proteasome subunit proteins were evaluated using the Biacore assay. The expression levels of proteasome subunits were determined using RT-PCR and Western blotting, and the levels of the integral 26S proteasome were evaluated using native PAGE analysis. Results: The proteomic analysis revealed that 1282 proteins were differentially expressed in BF211-treated A549 cells, and the putative target proteins of BF211 were associated with various cellular functions, including transcription, translation, mRNA splicing, ribosomal protein synthesis and proteasome function. In A549 cells, BF211 (5, 10, and 20 nmol/L) dose-dependently inhibited the enzymatic activities of proteasome. But BF211 displayed a moderate affinity in binding to proteasome beta 1 subunit and no binding affinity to the beta 2 and beta 5 subunits. Moreover, BF211 (0.1, 1, and 10 nmol/L) did not inhibit the proteasome activities in the cell lysates. BF211 (5, 10, and 20 nmol/L) significantly decreased the expression level of proteasome beta 1 subunit and the levels of integral 26S proteasome in A549 cells. Similarly, knockdown of the beta 1 subunit with siRNA in A549 cells significantly decreased integral 26S proteasome and proteasome activity. Conclusion: BF211 inhibits proteasome activity in A549 cells by decreasing beta 1 subunit expression and disrupting proteasome assembly.
资助项目	Shanghai Science & Technology Support Program[13431900401] ; Shanghai Science & Technology Innovation Action Program[15140904800] ; National Natural Science Foundation of China[81373964] ; National Science & Technology Major Project of China[2014ZX09301-306-03]
WOS关键词	20S PROTEASOME ; 26S PROTEASOME ; BREAST-CANCER ; DNA-DAMAGE ; APOPTOSIS ; PROTEIN ; AGENTS ; PROTEOLYSIS ; MECHANISM ; CARCINOMA
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5743038
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000379430900006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275969]
专题	上海中药现代化研究中心
通讯作者	Hu, Li-hong; Guo, De-an; Liu, Xuan
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Sun, Peng,Feng, Li-xing,Zhang, Dong-mei,et al. Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting beta 1 subunit expression and disrupting proteasome assembly[J]. ACTA PHARMACOLOGICA SINICA,2016,37(7):908-918.
APA	Sun, Peng.,Feng, Li-xing.,Zhang, Dong-mei.,Liu, Miao.,Liu, Wang.,...&Liu, Xuan.(2016).Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting beta 1 subunit expression and disrupting proteasome assembly.ACTA PHARMACOLOGICA SINICA,37(7),908-918.
MLA	Sun, Peng,et al."Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting beta 1 subunit expression and disrupting proteasome assembly".ACTA PHARMACOLOGICA SINICA 37.7(2016):908-918.