静态菌通过通过抑制A2B/CAMP/ERK轴促进FBXW7介导的MCL-1降解来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
影响因子:4.70000
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
摘要
化学疗法对结肠癌的耐药性是该疾病临床管理中不可避免的障碍。木质素是一种腺苷类似物，通过促进髓样细胞白血病1（MCL-1）蛋白质降解，在人类结肠癌细胞的化学敏感性中发挥了重要作用。但是，详细的机制仍有待进一步阐明。我们发现静态环菌上调了含有7（FBXW7）的F-box和WD重复域的表达，这是一种参与MCL-1降解的泛素连接酶。转录组测序分析表明，绿地环菌素显着抑制循环腺苷单磷酸（CAMP）和细胞外调节的蛋白激酶（ERK）下游信号途径中的结肠癌细胞中的蛋白质激酶（ERK），从而增强了FBXW7表达，从而增强了Mcl-1蛋白质的泛素化。我们验证了绿地菌通过与腺苷受体A2B的竞争结合来调节细胞内cAMP的水平。分子对接测定法也验证了结合关系。通过降低细胞内cAMP水平，绿地环蛋白阻止了下游信号通路的激活，从而最终通过抑制其启动子DNA甲基化而提高FBXW7表达来增强结肠癌细胞的药物敏感性。腺苷受体A2B的敲除和BR-cAMP治疗都可以有效地衰减绿地环霉素在体外和体内的功能。这项研究澄清说，静态菌通过通过抑制A2B/CAMP/ERK轴促进FBXW7介导的MCL-1降解来增强结肠癌细胞的药物敏感性，从而进一步了解静态应用。
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.