一种靶向 CHI3L1 的小分子通过阻断 IL-13Rα2 介导的 JNK-AP-1 信号来抑制肺转移。,Molecular Oncology

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一种靶向 CHI3L1 的小分子通过阻断 IL-13Rα2 介导的 JNK-AP-1 信号来抑制肺转移。
Molecular Oncology ( IF 5.0 ) Pub Date : 2021-11-24 , DOI: 10.1002/1878-0261.13138
Yong Sun Lee ₁ , Ji Eun Yu ₁ , Ki Cheon Kim ₁ , Dong Hun Lee ₁ , Dong Ju Son ₁ , Hee Pom Lee ₁ , Jae-Kyung Jung ₁ , Nam Du Kim ₂ , Young Wan Ham ₃ , Jaesuk Yun ₁ , Sang-Bae Han ₁ , Jin Tae Hong ₁

Affiliation

我们之前的大数据分析显示几丁质酶 3 like1 (CHI3L1) 表达与肺肿瘤发展之间存在高度关联。在本研究中，我们研究了 CHI3L1 抑制化学物质 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro -2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284)，可抑制肺转移并研究其作用机制。我们在体外和体内研究了 K284 的抗肿瘤作用。在体内模型中，K284（0.5 mg·kg-1 体重）在注射鼠黑色素瘤细胞 (B16F10) 或腺癌细胞人肺泡基底上皮细胞 (A549) 后显着抑制肺转移。K284 显着且浓度依赖性地抑制 A549 和 H460 肺癌细胞系中的癌细胞增殖和迁移。我们发现 K284 与 CHI3L1 的几丁质结合域 (CBD) 的结合阻止了 CHI3L1 与其受体白细胞介素 13 受体亚基 α-2 (IL-13Rα2) 的结合，从而抑制了 CHI3L1 信号。这种 CHI3L1-IL-13Rα2 信号的阻断导致 c-Jun N-末端激酶 (JNK)-激活蛋白 1 (AP-1) 信号的抑制，从而防止肺转移和癌细胞生长。我们的数据表明，K284 可作为靶向 CHI3L1 的潜在候选抗癌化合物。从而防止肺转移和癌细胞生长。我们的数据表明，K284 可作为靶向 CHI3L1 的潜在候选抗癌化合物。从而防止肺转移和癌细胞生长。我们的数据表明，K284 可作为靶向 CHI3L1 的潜在候选抗癌化合物。

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A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL-13Rα2-mediated JNK-AP-1 signals.

Our previous big data analyses showed a high level of association between chitinase 3 like1 (CHI3L1) expression and lung tumor development. In the present study, we investigated whether a CHI3L1-inhibiting chemical, 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284), could inhibit lung metastasis and studied its mechanism of action. We investigated the antitumor effect of K284 both in vitro and in vivo. K284 (0.5 mg·kg-1 body weight) significantly inhibited lung metastasis in in vivo models after injection of murine melanoma cells (B16F10) or adenocarcinomic human alveolar basal epithelial cells (A549). K284 significantly and concentration-dependently also inhibited cancer cell proliferation and migration in the A549 and H460 lung cancer cell lines. We found that the binding of K284 to the chitin-binding domain (CBD) of CHI3L1 prevented the binding of CHI3L1 to its receptor, interleukin-13 receptor subunit alpha-2 (IL-13Rα2), thereby suppressing the CHI3L1 signal. This blocking of the CHI3L1-IL-13Rα2 signal caused the inhibition of c-Jun N-terminal kinase (JNK)-activator protein 1 (AP-1) signals, resulting in the prevention of lung metastasis and cancer cell growth. Our data demonstrate that K284 may serve as a potential candidate anticancer compound targeting CHI3L1.

更新日期：2021-11-10

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