结肠癌化疗耐药是该疾病临床治疗中不可避免的障碍。 Clitocine 是一种腺苷类似物，通过促进 MCL-1 蛋白降解，在人结肠癌细胞的化疗敏感性中发挥重要作用。但具体机制仍有待进一步阐明。我们发现，clitocine 上调 FBXW7 的表达，FBXW7 是一种参与 MCL-1 降解的泛素连接酶。转录组测序分析显示，clitocine 显着抑制结肠癌细胞中的 cAMP 和 ERK 下游信号通路，从而增强 FBXW7 的表达，进而促进 MCL-1 蛋白的泛素化降解。我们验证了山药碱通过与腺苷受体 A2B 竞争性结合来调节细胞内 cAMP 水平。分子对接实验也验证了结合关系。通过降低细胞内 cAMP 水平，clitocine 阻断下游信号通路的激活，最终通过抑制其启动子 DNA 甲基化而增加 FBXW7 的表达，从而增强结肠癌细胞的药物敏感性。腺苷受体A2B敲除和Br-cAMP治疗均能有效减弱阴核碱在体外和体内的功能。本研究阐明，青柠碱通过抑制A2B/cAMP/ERK轴，促进FBXW7介导的MCL-1降解，从而增强结肠癌细胞的药物敏感性，为青青碱的临床应用提供了进一步的认识。

Chemotherapy resistance to colon cancer is an unavoidable obstacle in the clinical management of the disease. Clitocine, an adenosine analog, played a significant role in the chemosensitivity of human colon cancer cells by promoting MCL-1 protein degradation. However, the detailed mechanism remains to be further elucidated. We found that clitocine up-regulates the expression of FBXW7, a ubiquitin ligase involved in the MCL-1 degradation. Transcriptome sequencing analysis revealed that clitocine significantly inhibits the cAMP and ERK downstream signaling pathways in colon cancer cells, thereby enhancing FBXW7 expression and subsequently promoting the ubiquitination degradation of MCL-1 protein. We verified that clitocine regulated intracellular cAMP levels by competitive binding with the adenosine receptor A2B. Molecular docking assay also verified the binding relationship. By decreasing intracellular cAMP levels, clitocine blocks the activation of downstream signaling pathways, which ultimately enhances the drug sensitivity of colon cancer cells through increased FBXW7 expression due to the inhibition of its promoter DNA methylation. Both knock-out of adenosine receptor A2B and Br-cAMP treatment can effectively attenuate the function of clitocine in vitro and in vivo. This study clarified that clitocine enhanced the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis, providing further knowledge of the clinical application for clitocine.