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

Abstract

Background: The KITENIN/ErbB4 complex has been reported to participate in metastasis, which is the principal reason of death in most colorectal cancer patients.

Purpose: 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.

Methods: Using in vitro, in vivo, molecular-docking, and metabolomics studies, we evaluated the anticancer effect of emodin alone or in combination with DKCC14S.

Results: 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.

Conclusion: 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.

Keywords: Emodin; Energy metabolism; ErbB4; KITENIN (VANGL1); KSRP; Metastasis.