Atractyloside targets cancer-associated fibroblasts and inhibits the metastasis of colon cancer

Abstract

BackgroundSeveral evidences have proved that cancer-associated fibroblasts (CAFs) play a crucial role in tumor progression. In fact, CAFs form a major component of tumor microenvironment (TME). Therefore, the development and metastasis of tumors can be effectively inhibited by small molecular compounds that target CAFs.MethodsIn this study, we mainly analyzed the expression profile of colon cancer (CC). We determined the intensity of CAFs in CC tissues by using the immune cell infiltration score. Gene enrichment analysis and the screening of differentially expressed genes were performed on the basis of the intensity of CAFs in CC tissues. We screened the small molecular compounds that were converted from differentially expressed genes. The results indicated that atractyloside was a small molecular compound related to CAFs in CC tissues. We identified the relationship between atractylosides and CAFs through target protein analysis and network analysis, and verified the inhibition effect of atractylosides on CC cells (CCC) by migration assay and scratch wound-healing assays.ResultsWe found that many target proteins of atractyloside, such as the matrix metalloproteinase family and integrin proteins, were related to the biological function of CAFs. By performing network analysis, we found that the target proteins FGF1, ITGB1, and EDNRA were closely related to tumor angiogenesis, while the target proteins MMP9 and ITGAV were correlated to an extracellular matrix (ECM) and cell motility. These findings which further confirmed the relationship between atractylosides and CAFs. In addition, transwell cell migration and scratch wound-healing assays proved that atractylosides could significantly inhibit the migration of CCCs.ConclusionsThe atractyloside might be a small molecular compound that potentially targets CAFs and inhibits the development as well as metastasis of CC by changing the TME.