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A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells
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 inter...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891050/ https://www.ncbi.nlm.nih.gov/pubmed/26882566 http://dx.doi.org/10.18632/oncotarget.6990 |
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author | Fu, Zhi-guang Wang, Li Cui, Hong-yong Peng, Jian-long Wang, Shi-jie Geng, Jie-jie Liu, Ji-de Feng, Fei Song, Fei Li, Ling Zhu, Ping Jiang, Jian-li Chen, Zhi-nan |
author_facet | Fu, Zhi-guang Wang, Li Cui, Hong-yong Peng, Jian-long Wang, Shi-jie Geng, Jie-jie Liu, Ji-de Feng, Fei Song, Fei Li, Ling Zhu, Ping Jiang, Jian-li Chen, Zhi-nan |
author_sort | Fu, Zhi-guang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4891050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-48910502016-06-20 A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells Fu, Zhi-guang Wang, Li Cui, Hong-yong Peng, Jian-long Wang, Shi-jie Geng, Jie-jie Liu, Ji-de Feng, Fei Song, Fei Li, Ling Zhu, Ping Jiang, Jian-li Chen, Zhi-nan Oncotarget Research Paper 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. Impact Journals LLC 2016-01-23 /pmc/articles/PMC4891050/ /pubmed/26882566 http://dx.doi.org/10.18632/oncotarget.6990 Text en Copyright: © 2016 Fu et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Fu, Zhi-guang Wang, Li Cui, Hong-yong Peng, Jian-long Wang, Shi-jie Geng, Jie-jie Liu, Ji-de Feng, Fei Song, Fei Li, Ling Zhu, Ping Jiang, Jian-li Chen, Zhi-nan A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells |
title | A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells |
title_full | A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells |
title_fullStr | A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells |
title_full_unstemmed | A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells |
title_short | A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells |
title_sort | novel small-molecule compound targeting cd147 inhibits the motility and invasion of hepatocellular carcinoma cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891050/ https://www.ncbi.nlm.nih.gov/pubmed/26882566 http://dx.doi.org/10.18632/oncotarget.6990 |
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