Emodin disrupts the KITENIN oncogenic complex by binding ErbB4 and suppresses colorectal cancer progression in dual blockade with KSRP-binding compound.

The KITENIN/ErbB4 complex has been reported to participate in metastasis, which is the principal reason of death in most colorectal cancer patients. New therapeutics need to be developed to suppress the malignant effects of the KITENIN/ErbB4 complex, which is related to drug resistance. The present study aimed to evaluate changes in cancer cell invasion capacity, transcriptional regulators, and cellular bioenergetics after targeting the KITENIN/ErbB4 complex with emodin. Moreover, we aimed to reveal the mechanistic effects of emodin and observe the dual blockade effects of ErbB4-targeted therapy with KH-type splicing regulatory protein (KSRP) and search for new alternative blockade pathways. Using in vitro, in vivo, molecular-docking, and metabolomics studies, we evaluated the anticancer effect of emodin alone or in combination with DKC C14S. Emodin treatment decreased KITENIN and ErbB4 protein levels. The dysfunctional KITENIN/ErbB4 complex suppressed KITENIN-mediated cell invasion and downregulated AP-1 activity, aerobic glycolysis, and the levels of transcriptional regulators associated with cell metabolism. We conclude that emodin targets the KITENIN/ErbB4 complex and offering a novel mechanism by which it disrupts KITENIN-mediated signaling. Furthermore, we were demonstrated that the dual blocking effect of emodin and DKC-C14S on the KITENIN complex showed synergistic effects in suppressing colorectal cancer progression under in cell-based and animal assay. The results suggest that co-treatment with ErbB4 and KSRP-binding compounds could constitute a potential strategy for controlling colorectal cancer progression by disrupting the KITENIN complex. [Display omitted] [ABSTRACT FROM AUTHOR]