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A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex
Molecular Cancer ( IF 27.7 ) Pub Date : 2021-05-26 , DOI: 10.1186/s12943-021-01368-w
Jeong A Bae 1 , Woo Kyun Bae 2, 3 , Sung Jin Kim 1 , Yoo-Seung Ko 1 , Keon Young Kim 1 , So-Yeon Park 4 , Young Hyun Yu 4 , Eun Ae Kim 5 , Ik Joo Chung 2, 3 , Hangun Kim 4 , Hyung-Ho Ha 4 , Kyung Keun Kim 1
Affiliation  

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.

中文翻译:

一种新的 KSRP 结合化合物通过靶向致癌 KITENIN 复合物抑制结直肠癌的远处转移

远处转移是结直肠癌(CRC)患者死亡的主要原因。以前,我们将 KITENIN 鉴定为一种转移增强基因,并提出致癌 KITENIN 复合物参与过表达 KITENIN 的 CRC 细胞的转移性传播。在这里,我们试图找到靶向 KITENIN 复合物的物质并测试它们抑制 CRC 远处转移的能力。我们筛选了一个小分子化合物库,以找到抑制 CRC 细胞中 KITENIN 复合物的候选物质。我们选择了一种候选化合物,并通过体外测定、分子对接模型和体内肿瘤模型检查了其对 KITENIN 复合物和远处转移的影响。在几种化合物中,我们将 DKC1125(KITENIN Complex #1125 分解剂)确定为最佳候选化合物。DKC1125 特异性抑制 KITENIN 功能增益。在结合 KH 型剪接调节蛋白 (KSRP) 后,DKC1125 通过招募 RACK1 和 miRNA-124 降解 KITENIN 和 Dvl2,导致功能性 KITENIN-KSRP-RACK1-Dvl2 复合物的解体。计算机对接模型表明 DKC1125 与 KSRP 的第四个 KH 域的结合口袋特异性相互作用。KITENIN 过表达的 CRC 细胞使某些 microRNA 失调,并对 5-氟尿嘧啶、奥沙利铂和西妥昔单抗产生耐药性。DKC1125 通过使失调的 microRNA(包括 miRNA-124)的表达正常化来恢复对这些药物的敏感性。DKC1125 在小鼠模型中有效抑制结直肠肝转移。有趣的是,DKC1125 与 5-氟尿嘧啶的组合比单独使用任何一种药物更有效地抑制了转移。
更新日期:2021-05-26
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