A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells

doi:10.18632/oncotarget.6990

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 新药研究国家重点实验室

	A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells
	Fu, Zhi-guang 2,3; Wang, Li 4; Cui, Hong-yong 2,3; Peng, Jian-long 5; Wang, Shi-jie 2,3; Geng, Jie-jie 2,3; Liu, Ji-de 2,3; Feng, Fei 2,3; Song, Fei 2,3; Li, Ling 2,3
刊名	ONCOTARGET
	2016-02-23
卷号	7 期号:8 页码:9430-9448
关键词	CD147 small molecule inhibitor hepatocellular carcinoma cells metastasis dimerization
ISSN号	1949-2553
DOI	10.18632/oncotarget.6990
文献子类	Article
英文摘要	CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression.
资助项目	National Basic Research Program[2015CB553701] ; National ST Major Project[2013ZX09301301] ; National High Technology Research and Development Program of China[2012AA020302] ; National Natural Science Foundation of China[81102259] ; National Natural Science Foundation of China[81201774] ; National Natural Science Foundation of China[31270015]
WOS关键词	PROTEIN-PROTEIN INTERACTIONS ; POOR-PROGNOSIS ; CLINICAL-IMPLICATIONS ; SIGNALING PATHWAYS ; EMMPRIN EXPRESSION ; KINASE INHIBITORS ; CANCER STATISTICS ; PROSTATE-CANCER ; HAB18G/CD147 ; METASTASIS
WOS研究方向	Oncology ; Cell Biology
语种	英语
出版者	IMPACT JOURNALS LLC
WOS记录号	WOS:000375618100073
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276138]
专题	新药研究国家重点实验室中科院受体结构与功能重点实验室
通讯作者	Jiang, Jian-li; Chen, Zhi-nan
作者单位	1.Fourth Mil Med Univ, Dept Clin Immunol, PLA Specialized Res Inst Rheumatol & Immunol, Xijing Hosp, Xian 710032, Peoples R China 2.Fourth Mil Med Univ, Cell Engn Res Ctr, Xian 710032, Peoples R China; 3.Fourth Mil Med Univ, Dept Cell Biol, State Key Lab Canc Biol, Natl Key Discipline Cell Biol, Xian 710032, Peoples R China; 4.Fourth Mil Med Univ, State Key Lab Canc Biol, Dept Pharmacogen, Sch Pharm, Xian 710032, Peoples R China; 5.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China;
推荐引用方式 GB/T 7714	Fu, Zhi-guang,Wang, Li,Cui, Hong-yong,et al. A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells[J]. ONCOTARGET,2016,7(8):9430-9448.
APA	Fu, Zhi-guang.,Wang, Li.,Cui, Hong-yong.,Peng, Jian-long.,Wang, Shi-jie.,...&Chen, Zhi-nan.(2016).A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells.ONCOTARGET,7(8),9430-9448.
MLA	Fu, Zhi-guang,et al."A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells".ONCOTARGET 7.8(2016):9430-9448.