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

Zhi-Guang Fu,Fei Feng,Zhi-Nan Chen,Hong-Yong Cui,Jie-Jie Geng,Shi-Jie Wang,Ling Li,Fei Song,Li Wang,Jian-Long Peng,Ping Zhu,Ji-De Liu,Jian-Li Jiang

doi:10.18632/oncotarget.6990

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common cancers and is the frequent cause of cancer-related death in the world [1]
Despite the progress made in elucidating the molecular events underlying metastasis [5,6], relapse rates remain high after HCC resection, and relapse nearly always originates from metastases [7]
We observed that AC-73 notably reduced p-ERK1/2 and p-signal transducer and activator of transcription 3 (STAT3) in the two parental HCC cell lines, but not the HCC CD147-/- lines, indicating that AC-73 inhibits ERK/STAT3 signaling via specific binding to CD147. Considering about both STAT3 and ERK signaling are implicated in cell growth, we evaluated the effect of AC-73 on HCC proliferation in vitro and found no obvious effect when the concentrations of AC-73 is less than 20 μM within 7 days (Supplementary Figure S3A)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common cancers and is the frequent cause of cancer-related death in the world [1]. Despite significant improvement in both diagnostic and therapeutic modalities for cancer patients, metastasis still represents the major cause of cancer mortality [3]. It is well known that metastasis involves a series of interrelated events, www.impactjournals.com/oncotarget including loss of the ability of cancer cells to adhere to their native tissue, invasion into the surrounding extracellular matrix, migration, and proliferation at a secondary site [4]. Despite the progress made in elucidating the molecular events underlying metastasis [5,6], relapse rates remain high after HCC resection, and relapse nearly always originates from metastases [7]. Our inability to combat HCC invasion and metastasis has become a major obstacle to the survival and the quality of life in HCC patients [8]

Methods

Results

Conclusion