Shen Dan, Zeng Yuanyuan, Zhang Weijie, Li Yue, Zhu Jianjie, Liu Zeyi, Yan Zhaowei, Huang Jian-An
Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China; Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China.
Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China.
Eur J Pharmacol. 2022 May 15;923:174925. doi: 10.1016/j.ejphar.2022.174925. Epub 2022 Mar 30.
Lung cancer is the leading cause of cancer-associated death worldwide and is classified into non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC accounts for approximately 80%-85% of all lung cancer cases. Chenodeoxycholic acid (CDCA), a primary bile acid, has been reported to inhibit carcinoma cell proliferation. Here, we aimed to determine the effects and mechanism of action of CDCA against lung adenocarcinoma (LUAD).
Western blotting and quantitative real-time polymerase chain reaction were used to evaluate the protein and mRNA expression levels in LUAD cell lines, respectively. Cell Counting Kit-8 and clone formation assays were performed to evaluate the proliferation ability of different cell types in vitro. Tumor cell motility was evaluated using Transwell assays. The transcriptional profile of A549 cells treated with CDCA was determined through RNA sequencing analysis. A xenograft model was established to evaluate the effects of CDCA on LUAD progression in vivo.
CDCA inhibited LUAD cell proliferation, migration, and invasion. Furthermore, it promoted apoptosis in LUAD cells. Mechanistically, CDCA inhibited the integrin α5β1 signaling pathway in LUAD cells by inhibiting the expression of the α5 and β1 subunits of integrin and phosphorylated FAK. Moreover, CDCA induced an increase in the levels of p53, a downstream gene of the integrin α5β1/FAK pathway. In addition, CDCA significantly decreased tumor volume in mice without inducing significant toxicity.
Our findings indicate that CDCA attenuates LUAD pathogenesis in vitro and in vivo via the integrin α5β1/FAK/p53 axis.
肺癌是全球癌症相关死亡的主要原因，分为非小细胞肺癌（NSCLC）和小细胞肺癌（SCLC）。NSCLC约占所有肺癌病例的80%-85%。鹅去氧胆酸（CDCA）是一种初级胆汁酸，据报道可抑制癌细胞增殖。在此，我们旨在确定CDCA对肺腺癌（LUAD）的作用及其作用机制。
分别采用蛋白质印迹法和定量实时聚合酶链反应评估LUAD细胞系中的蛋白质和mRNA表达水平。使用细胞计数试剂盒-8和克隆形成试验评估不同细胞类型在体外的增殖能力。使用Transwell试验评估肿瘤细胞的运动能力。通过RNA测序分析确定用CDCA处理的A549细胞的转录谱。建立异种移植模型以评估CDCA对LUAD体内进展的影响。
CDCA抑制LUAD细胞的增殖、迁移和侵袭。此外，它还促进LUAD细胞的凋亡。机制上，CDCA通过抑制整合素α5和β1亚基以及磷酸化FAK的表达来抑制LUAD细胞中的整合素α5β1信号通路。此外，CDCA诱导整合素α5β1/FAK通路的下游基因p53水平升高。此外，CDCA显著降低小鼠肿瘤体积，且未诱导明显毒性。
我们的研究结果表明，CDCA通过整合素α5β1/FAK/p53轴在体外和体内减轻LUAD的发病机制。
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