A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex
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....
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-05-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-021-01368-w |
| _version_ | 1818641850488061952 |
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| author | Jeong A Bae Woo Kyun Bae Sung Jin Kim Yoo-Seung Ko Keon Young Kim So-Yeon Park Young Hyun Yu Eun Ae Kim Ik Joo Chung Hangun Kim Hyung-Ho Ha Kyung Keun Kim |
| author_facet | Jeong A Bae Woo Kyun Bae Sung Jin Kim Yoo-Seung Ko Keon Young Kim So-Yeon Park Young Hyun Yu Eun Ae Kim Ik Joo Chung Hangun Kim Hyung-Ho Ha Kyung Keun Kim |
| author_sort | Jeong A Bae |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T23:33:43Z |
| format | Article |
| id | doaj.art-b5fa0e743f4e494eaffee6fb0381331c |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-16T23:33:43Z |
| publishDate | 2021-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-b5fa0e743f4e494eaffee6fb0381331c2022-12-21T22:11:48ZengBMCMolecular Cancer1476-45982021-05-0120112410.1186/s12943-021-01368-wA new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complexJeong A Bae0Woo Kyun Bae1Sung Jin Kim2Yoo-Seung Ko3Keon Young Kim4So-Yeon Park5Young Hyun Yu6Eun Ae Kim7Ik Joo Chung8Hangun Kim9Hyung-Ho Ha10Kyung Keun Kim11Department of Pharmacology, Chonnam National University Medical SchoolDepartment of Hematology-Oncology, Chonnam National University Medical SchoolDepartment of Pharmacology, Chonnam National University Medical SchoolDepartment of Pharmacology, Chonnam National University Medical SchoolDepartment of Pharmacology, Chonnam National University Medical SchoolCollege of Pharmacy, Sunchon National UniversityCollege of Pharmacy, Sunchon National UniversityCollege of Pharmacy, Chosun UniversityDepartment of Hematology-Oncology, Chonnam National University Medical SchoolCollege of Pharmacy, Sunchon National UniversityCollege of Pharmacy, Sunchon National UniversityDepartment of Pharmacology, Chonnam National University Medical SchoolAbstract 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.https://doi.org/10.1186/s12943-021-01368-wColorectal cancerKITENIN complexKSRPMetastasismicroRNA |
| spellingShingle | Jeong A Bae Woo Kyun Bae Sung Jin Kim Yoo-Seung Ko Keon Young Kim So-Yeon Park Young Hyun Yu Eun Ae Kim Ik Joo Chung Hangun Kim Hyung-Ho Ha Kyung Keun Kim A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex Molecular Cancer Colorectal cancer KITENIN complex KSRP Metastasis microRNA |
| title | A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex |
| title_full | A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex |
| title_fullStr | A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex |
| title_full_unstemmed | A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex |
| title_short | A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex |
| title_sort | new ksrp binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic kitenin complex |
| topic | Colorectal cancer KITENIN complex KSRP Metastasis microRNA |
| url | https://doi.org/10.1186/s12943-021-01368-w |
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