A novel synthetic small molecule YH-306 suppresses colorectal tumour growth and metastasis via FAK pathway.

Fujun Dai,Li Huang,Yihua Chen,Mingyao Liu,Zhengfang Yi,Jingjie Li,Weiguang Tong,Tao Zhang,Jinhua Wang

doi:10.1111/jcmm.12450

Abstract

Cell migration and invasion are key processes in the metastasis of cancer, and suppression of these steps is a promising strategy for cancer therapeutics. The aim of this study was to explore small molecules for treating colorectal cancer (CRC) and to investigate their anti-metastatic mechanisms. In this study, six CRC cell lines were used. We showed that YH-306 significantly inhibited the migration and invasion of CRC cells in a dose-dependent manner. In addition, YH-306 inhibited cell adhesion and protrusion formation of HCT116 and HT-29 CRC cells. Moreover, YH-306 potently suppressed uninhibited proliferation in all six CRC cell lines tested and induced cell apoptosis in four cell lines. Furthermore, YH-306 inhibited CRC colonization in vitro and suppressed CRC growth in a xenograft mouse model, as well as hepatic/pulmonary metastasis in vivo. YH-306 suppressed the activation of focal adhesion kinase (FAK), c-Src, paxillin, and phosphatidylinositol 3-kinases (PI3K), Rac1 and the expression of matrix metalloproteases (MMP) 2 and MMP9. Meanwhile, YH-306 also inhibited actin-related protein (Arp2/3) complex-mediated actin polymerization. Taken together, YH-306 is a candidate drug in preventing growth and metastasis of CRC by modulating FAK signalling pathway.

Highlights

Screening, surgical resection and adjuvant therapy have improved the outcome for patients with colorectal cancer (CRC), CRC is still the third-leading cause of cancer-related deaths [1]
focal adhesion kinase (FAK) is a critical mediator in regulating cell motility including cell adhesion, spreading, migration and invasion, we found that the phosphorylation of FAK and paxillin was significantly reduced by YH-306 for 60 min. in cells exposed to fibronectin (Fig. 7A)
We demonstrated that a novel synthetic small molecule, YH-306, inhibited colorectal tumour growth and hepatic/pulmonary metastasis

Summary

Introduction

Surgical resection and adjuvant therapy have improved the outcome for patients with colorectal cancer (CRC), CRC is still the third-leading cause of cancer-related deaths [1]. More than 140,000 new cases of CRC were estimated and more than 50,000 individuals will die from CRC during 2013 in the United States [2] To address this conundrum, many studies focused on research for new therapies to target metastatic progression, as metastasis from the primary site of tumour growth to distant organs was the leading cause of cancer-related mortality [3]. The adhesion of cells onto specific extracellular matrix (ECM) components induces the formation of focal adhesions, followed by the recruitment of cytoplasmic proteins, such as focal adhesion kinase (FAK), c-Src, cdc, Rac, paxillin and talin [6]. Among these molecules, the FAK/Src complex mediates signalling by binding to and phosphorylating downstream molecules. The initiation of cell adhesion and focal adhesions is associated with the small G-proteins Rho, cdc and Rac, which regulate actin cytoskeleton a 2015 The Authors

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