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A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex
- Source :
- Molecular Cancer, Molecular Cancer, Vol 20, Iss 1, Pp 1-24 (2021)
- Publication Year :
- 2021
- Publisher :
- BioMed Central, 2021.
-
Abstract
- Background 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. Methods 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. Results 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. Conclusion 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Colorectal cancer
Antineoplastic Agents
Biology
Metastasis
03 medical and health sciences
Mice
0302 clinical medicine
In vivo
microRNA
Drug Discovery
medicine
Animals
Humans
KSRP
Neoplasm Metastasis
RC254-282
Regulation of gene expression
Cetuximab
Research
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Membrane Proteins
RNA-Binding Proteins
medicine.disease
Molecular Docking Simulation
030104 developmental biology
Oncology
Docking (molecular)
030220 oncology & carcinogenesis
RNA splicing
KITENIN complex
Cancer research
Trans-Activators
Molecular Medicine
Carrier Proteins
Colorectal Neoplasms
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14764598
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer
- Accession number :
- edsair.doi.dedup.....3e26c5685588b60c644ceff13ac795f4