Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China.
Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167440. doi: 10.1016/j.bbadis.2024.167440. Epub 2024 Jul 24.
Cancer stem cells (CSCs) are responsible for tumor chemoresistance, and the aryl hydrocarbon receptor (AHR) is indispensable for maintaining CSC characteristics. Here, we aimed to investigate how the interaction between progesterone receptor membrane component 1 (PGRMC1) and AHR contributes to the maintenance of CSC phenotypes in non-small cell lung cancer (NSCLC). Clinical data and tissue microarray analyses indicated that patients with elevated PGRMC1 expression had poorer prognoses. Moreover, PGRMC1 overexpression enhanced CSC phenotypes and chemotherapy resistance in vitro and in vivo by modulating AHR ubiquitination. We then determined the specific interaction sites between PGRMC1 and AHR. Mass spectrometry screening identified tripartite motif containing 56 (TRIM56) as the E3 ligase targeting AHR. Notably, PGRMC1 overexpression inhibited the interaction between TRIM56 and AHR. Overall, our study revealed a regulatory mechanism that involves PGRMC1, AHR, and TRIM56, providing insights for developing CSC-targeting strategies in NSCLC treatment.
癌症干细胞 (CSCs) 是肿瘤化疗耐药的罪魁祸首，而芳香烃受体 (AHR) 对于维持 CSC 特征是不可或缺的。在这里，我们旨在研究孕激素膜受体成分 1 (PGRMC1) 和 AHR 之间的相互作用如何有助于维持非小细胞肺癌 (NSCLC) 中的 CSC 表型。临床数据和组织微阵列分析表明，PGRMC1 表达升高的患者预后较差。此外，PGRMC1 的过表达通过调节 AHR 泛素化增强了体外和体内的 CSC 表型和化疗耐药性。然后，我们确定了 PGRMC1 和 AHR 之间的特定相互作用位点。质谱筛选鉴定了三部分基序包含蛋白 56 (TRIM56) 作为 AHR 的 E3 连接酶。值得注意的是，PGRMC1 的过表达抑制了 TRIM56 和 AHR 之间的相互作用。总的来说，我们的研究揭示了一个涉及 PGRMC1、AHR 和 TRIM56 的调节机制，为 NSCLC 治疗中靶向 CSC 的策略提供了新的见解。
