ABSTRACT
Dysregulation of cancer cell motility is a key driver of invasion and metastasis. High dysadherin expression in cancer cells is correlated with invasion and metastasis. Here, we found the molecular mechanism by which dysadherin regulates the migration and invasion of colon cancer (CC). Comprehensive analysis using single-cell RNA sequencing data from CC patients revealed that high dysadherin expression in cells is linked to cell migration-related gene signatures. We confirmed that the deletion of dysadherin in tumor cells hindered local invasion and distant migration using in vivo tumor models. In this context, by performing cell morphological analysis, we found that aberrant cell migration resulted from impaired actin dynamics, focal adhesion turnover and protrusive structure formation upon dysadherin expression. Mechanistically, the activation of focal adhesion kinase (FAK) was observed in dysadherin-enriched cells. The dysadherin/FAK axis enhanced cell migration and invasion by activating the FAK downstream cascade, which includes the Rho family of small GTPases. Overall, this study illuminates the role of dysadherin in modulating cancer cell migration by forcing actin dynamics and protrusive structure formation via FAK signaling, indicating that targeting dysadherin may be a potential therapeutic strategy for CC patients.
Subject(s)
Cell Movement , Colonic Neoplasms , Focal Adhesion Protein-Tyrosine Kinases , Ion Channels , Microfilament Proteins , Animals , Humans , Mice , Cell Line, Tumor , Cell Movement/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Colonic Neoplasms/genetics , Focal Adhesion Kinase 1/metabolism , Focal Adhesion Kinase 1/genetics , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Ion Channels/metabolism , Ion Channels/genetics , Microfilament Proteins/metabolism , Microfilament Proteins/genetics , Signal TransductionABSTRACT
As a part of our search for hepatoprotective compounds from Lycium chinense fruits, three new pyrrole derivatives (1-3) were isolated. These compounds and a related synthetic methylated compound (4) were evaluated for their biological activity and structure-activity relationship, and compounds 1 and 2 showed hepatoprotective effects comparable to silybin at the concentration of 0.1 microM (64.4 and 65.8%, respectively).
