Clitocine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
Clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis
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影响因子:4.7
分区:生物学3区 / 细胞生物学3区 生理学3区
发表日期:2024 Oct 01
作者:
Feng Ruan, Yanyun Ruan, Huamin Gu, Jianguo Sun, Qi Chen
DOI:
10.1152/ajpcell.00310.2024
摘要
结肠癌的化疗耐药是临床治疗中的一大难题。Clitocine，一种腺苷类似物，在增强人类结肠癌细胞的化疗敏感性方面发挥了重要作用，机制为促进髓系细胞白血病蛋白1（MCL-1）蛋白的降解。然而，具体机制尚需进一步阐明。我们发现，Clitocine上调了参与MCL-1降解的泛素连接酶FBXW7的表达。转录组测序分析显示，Clitocine显著抑制结肠癌细胞中环腺苷酸（cAMP）和细胞外调节蛋白激酶（ERK）下游信号通路，从而增强FBXW7的表达并促进MCL-1蛋白的泛素化降解。通过竞争结合腺苷受体A2B，验证了Clitocine调控细胞内cAMP水平的作用，并通过分子对接验证了其结合关系。Clitocine通过降低细胞内cAMP水平，阻断下游信号通路的激活，从而通过抑制其启动子DNA甲基化，增加FBXW7的表达，最终增强结肠癌细胞的药物敏感性。敲除腺苷受体A2B或使用Br-cAMP均能有效减弱Clitocine的作用，无论在体内还是体外。本研究明确了Clitocine通过抑制A2B/cAMP/ERK轴，促进FBXW7介导的MCL-1降解，增强结肠癌细胞的药物敏感性，为Clitocine的临床应用提供了新的认识。新颖与意义：本研究发现，Clitocine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。
Abstract
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 myeloid cell leukemia 1 (MCL-1) protein degradation. However, the detailed mechanism remains to be further elucidated. We found that clitocine upregulates the expression of F-box and WD repeat domain containing 7 (FBXW7), a ubiquitin ligase involved in the MCL-1 degradation. Transcriptome sequencing analysis revealed that clitocine significantly inhibits the cyclic adenosine monophosphate (cAMP) and extracellular regulated protein kinases (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. A 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 knockout of the 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.NEW & NOTEWORTHY Our study found that clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis.