期刊
MOLECULAR CANCER
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12943-021-01368-w
关键词
Colorectal cancer; KITENIN complex; KSRP; Metastasis; microRNA
资金
- National Research Foundation of Korea - Korea government (MSIT) [NRF-2019M3E5D5050371, 2020R1A2C2007189]
- National Research Foundation of Korea [NRF-2018R1D1A1B07049439]
- Bio & Medical Technology Development Program of the National Research Foundation of Korea [NRF-2020M3A9G3080281]
- National Research Foundation of Korea [2020R1A2C2007189] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The study identified DKC1125 as an effective candidate drug for suppressing distant metastasis in colorectal cancer by disintegrating the KITENIN complex. DKC1125 also restored sensitivity to common chemotherapy drugs, showing promise as a novel therapeutic option for CRC patients with high levels of KITENIN.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据