A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex

• Published in: Molecular cancer Vol. 20; no. 1; p. 78
• Main Authors: Bae, Jeong A, Bae, Woo Kyun, Kim, Sung Jin, Ko, Yoo-Seung, Kim, Keon Young, Park, So-Yeon, Yu, Young Hyun, Kim, Eun Ae, Chung, Ik Joo, Kim, Hangun, Ha, Hyung-Ho, Kim, Kyung Keun
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26.05.2021; BioMed Central; BMC
• Subjects: 5-Fluorouracil; Acids; Analysis; Animal models; Animals; Antibodies; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Blood proteins; Cancer therapies; Carrier Proteins - drug effects; Chromatography; Cloning; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Dishevelled protein; Drug Discovery; Fluorouracil; Humans; KITENIN complex; KSRP; Liver; Membrane Proteins - drug effects; Metastases; Metastasis; Mice; MicroRNA; miRNA; Molecular Docking Simulation; Molecular modelling; Molecular weight; Neoplasm Metastasis - pathology; Oxaliplatin; Plasmids; Protein binding; Protein expression; Proteins; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - drug effects; RNA-Binding Proteins - metabolism; Trans-Activators - antagonists & inhibitors; Trans-Activators - drug effects; Trans-Activators - metabolism; Iran; South Korea; KITENIN complex; microRNA; Metastasis; KSRP; Colorectal cancer
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-021-01368-w

Distant metastasis is the major cause of death in patients with colorectal cancer (CRC). Previously, we identified KITENIN as a metastasis-enhancing gene and suggested that the oncogenic KITENIN complex is involved in metastatic dissemination of KITENIN-overexpressing CRC cells. Here, we attempted to find substances targeting the KITENIN complex and test their ability to suppress distant metastasis of CRC. We screened a small-molecule compound library to find candidate substances suppressing the KITENIN complex in CRC cells. We selected a candidate compound and examined its effects on the KITENIN complex and distant metastasis through in vitro assays, a molecular docking model, and in vivo tumor models. Among several compounds, we identified DKC1125 (Disintegrator of KITENIN Complex #1125) as the best candidate. DKC1125 specifically suppressed KITENIN gain of function. After binding KH-type splicing regulatory protein (KSRP), DKC1125 degraded KITENIN and Dvl2 by recruiting RACK1 and miRNA-124, leading to the disintegration of the functional KITENIN-KSRP-RACK1-Dvl2 complex. A computer docking model suggested that DKC1125 specifically interacted with the binding pocket of the fourth KH-domain of KSRP. KITENIN-overexpressing CRC cells deregulated certain microRNAs and were resistant to 5-fluorouracil, oxaliplatin, and cetuximab. DKC1125 restored sensitivity to these drugs by normalizing expression of the deregulated microRNAs, including miRNA-124. DKC1125 effectively suppressed colorectal liver metastasis in a mouse model. Interestingly, the combination of DKC1125 with 5-fluorouracil suppressed metastasis more effectively than either drug alone. DKC1125 targets the KITENIN complex and could therefore be used as a novel therapeutic to suppress liver metastasis in CRC expressing high levels of KITENIN.