解整合素和金属蛋白酶结构域 10 (ADAM10) 是 ADAM 家族的成员，是一种具有潜在粘附和蛋白酶/转化酶功能的细胞表面蛋白。天然产物[腺苷(AD)及其类似物、虫草素(CD)和N6,N6-二甲基腺苷(m6 2A)]在癌症中的表达调节和免疫调节尚不清楚。结果，AD、CD 和 m6 2A 抑制了多种癌细胞系中 ADAM10 的表达，表明它们在抗癌药物中的作用。与 ADAM10 蛋白的进一步分子对接发现，所有对接基团的所有小分子（AD、CD 和 m6 2A）的结合能均 <-7 kcal/mol，表明具有非常好的结合活性。此外，对癌症中免疫调节作用的分析表明，在膀胱尿路上皮癌、胸腺瘤、乳腺浸润性癌、TGCT、肾肾乳头状细胞癌、SKCM 和甲状腺癌，表明 ADAM10 具有免疫促进作用。 AD 和 CD 体内 LAG3 mRNA 水平均降低。 ADAM10 还与肿瘤免疫抑制呈负相关，并与肿瘤的免疫浸润相关。总体而言，本研究确定了 AD、CD 和 m6 2A 以及癌症中 AD 或 CD/ADAM10/LAG3 信号传导中 ADAM10 的表达，并提出了一种通过使用小分子 AD、CD 和 m6 靶向 ADAM10 来进行癌症免疫治疗的潜在方法。 2A.版权所有 © 2024 张、付、杜、刘、程、伟、徐、付。

A disintegrin and metalloproteinase domain 10 (ADAM10), a member of the ADAM family, is a cellular surface protein with potential adhesion and protease/convertase functions. The expression regulations in cancers by natural products [adenosine (AD) and its analogs, cordycepin (CD), and N6, N6-dimethyladenosine (m6 2A)], and immune regulation are unclear. As results, AD, CD, and m6 2A inhibited ADAM10 expression in various cancer cell lines, indicating their roles in anti-cancer agents. Further molecular docking with ADAM10 protein found the binding energies of all docking groups were <-7 kcal/mol for all small-molecules (AD, CD and m6 2A), suggesting very good binding activities. In addition, analysis of the immunomodulatory roles in cancer showed that ADAM10 was negatively correlated with immunomodulatory genes such as CCL27, CCL14, CCL25, CXCR5, HLA-B, HLA-DOB1, LAG3, TNFRSF18, and TNFRSF4 in bladder urothelial carcinoma, thymoma, breast invasive carcinoma, TGCT, kidney renal papillary cell carcinoma, SKCM and thyroid carcinoma, indicating the immune-promoting roles for ADAM10. LAG3 mRNA levels were reduced by both AD and CD in vivo. ADAM10 is also negatively associated with tumor immunosuppression and interrelated with the immune infiltration of tumors. Overall, the present study determined ADAM10 expression by AD, CD and m6 2A, and in AD or CD/ADAM10/LAG3 signaling in cancers, and suggested a potential method for immunotherapy of cancers by targeting ADAM10 using the small molecules AD, CD and m6 2A.Copyright © 2024 Zhang, Fu, Du, Liu, Cheng, Wei, Xu and Fu.