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对药物的敏感性。

IF 5 2区 生物学 Q2 CELL BIOLOGY
Feng Ruan, Yanyun Ruan, Huamin Gu, Jianguo Sun, Qi Chen
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引用次数: 0

摘要

结肠癌的化疗耐药性是临床治疗中不可避免的障碍。腺苷类似物 Clitocine 通过促进 MCL-1 蛋白降解,在人类结肠癌细胞的化疗敏感性方面发挥了重要作用。然而,其具体机制仍有待进一步阐明。我们发现,氯托辛可上调参与MCL-1降解的泛素连接酶FBXW7的表达。转录组测序分析表明,氯托辛能显著抑制结肠癌细胞中的cAMP和ERK下游信号通路,从而提高FBXW7的表达,进而促进MCL-1蛋白的泛素化降解。我们验证了氯妥辛通过与腺苷受体 A2B 竞争性结合来调节细胞内 cAMP 水平。分子对接试验也验证了这种结合关系。通过降低细胞内cAMP水平,氯托辛阻断了下游信号通路的激活,最终通过抑制启动子DNA甲基化导致的FBXW7表达增加来提高结肠癌细胞对药物的敏感性。腺苷受体A2B的敲除和Br-cAMP处理都能有效地减弱氯托辛在体外和体内的作用。该研究阐明了氯妥辛通过抑制A2B/cAMP/ERK轴促进FBXW7介导的MCL-1降解,从而增强了结肠癌细胞对药物的敏感性,为氯妥辛的临床应用提供了进一步的知识。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis.

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.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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