PO.CH01.05 · 化学
槲皮素在多种人类癌细胞系中对内源性膜结合TRAIL的异质性表达及癌症选择性调控
Heterogeneous expression and cancer-selective regulation of endogenous membrane TRAIL by quercetin across various human cancer cell lines
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
我们近期研究表明，若干人类胶质母细胞瘤细胞系（M059K、T98G、A172）以及正常人星形胶质细胞均具有内源性肿瘤坏死因子相关凋亡诱导配体（TRAIL）。此外，我们证明黄酮类化合物槲皮素可促进内源性膜结合TRAIL（mTRAIL）向胶质母细胞瘤细胞质膜的转运，在质膜上它可与相邻癌细胞表面已存在的死亡受体相互作用，通过外源性和内源性两条通路触发凋亡。相反，尽管正常人星形胶质细胞同样表达内源性mTRAIL，但槲皮素处理并未增强其向质膜的转运，也未诱导凋亡。总之，这些观察结果提示槲皮素可选择性地激活癌细胞而非正常细胞中mTRAIL介导的凋亡（Thorpe等，Cancers 2025, 17, 3197; https://doi.org/10.3390/cancers17193197）。本研究探讨mTRAIL的表达及对槲皮素的响应是否可扩展至更广泛的人类癌症和非恶性细胞系谱系。我们采用蛋白质免疫印迹和流式细胞术评估了一组人类癌症和正常细胞系中mTRAIL的表达，包括乳腺癌（MCF-7、BT-20、HCC1937）、黑色素瘤（A375、MeWo、WM164）、Burkitt淋巴瘤（RA-1、DG-75、Daudi）、正常成纤维细胞（08398），以及目前正在研究的其他模型。在若干恶性和非恶性细胞系中检测到内源性mTRAIL，包括MCF-7、HCC1937、A375、RA-1、Daudi和08398成纤维细胞，而在BT-20、MeWo、WM164和DG-75中则未检出。在RA-1和A375癌细胞中，流式细胞术进一步证实槲皮素处理以浓度依赖方式增加了细胞表面mTRAIL，从而导致凋亡。综合我们此前已发表的研究数据，在12个人类癌细胞系中的8个（67%）以及全部3个非转化细胞系（100%）中均检测到内源性mTRAIL表达，表明其表达在不同癌细胞系之间可能存在差异，但在正常细胞中似乎较为一致。总体而言，这些发现支持槲皮素在促进mTRAIL转运及其在质膜上呈递方面的作用，最终导致相邻癌细胞的死亡。正在进行的研究旨在阐明内源性mTRAIL表达在各类细胞中的功能意义，并明确槲皮素促进mTRAIL向恶性而非正常细胞质膜转运的分子机制，以确立其在不同癌症类型中的潜在治疗意义。
查看英文原文 English abstract
We have recently shown that several human glioblastoma cell lines (M059K, T98G, A172), as well as normal human astrocytes, possess endogenous tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In addition, we demonstrated that the flavonoid quercetin promotes the trafficking of endogenous membrane TRAIL (mTRAIL) to the plasma membrane in glioblastoma cells, where it can interact with death receptors already present on the surface of neighboring cancer cells and trigger apoptosis through both the extrinsic and intrinsic pathways. In contrast, although normal human astrocytes also express endogenous mTRAIL, quercetin treatment did not enhance its trafficking to the plasma membrane or induce apoptosis. Together, these observations suggest that quercetin selectively activates mTRAIL-mediated apoptosis in cancer cells but not in normal cells ( Thorpe et al., Cancers 2025, 17, 3197; https://doi.org/10.3390/cancers17193197). The present study explores whether mTRAIL expression and responsiveness to quercetin extend across a broader spectrum of human cancer and non-malignant cell lines. Western blotting and flow cytometry were used to evaluate mTRAIL expression in a panel of human cancer and normal cell lines, including breast cancer (MCF-7, BT-20, HCC1937), melanoma (A375, MeWo, WM164), Burkitt lymphoma (RA-1, DG-75, Daudi), normal fibroblasts (08398), and additional models currently under investigation. Endogenous mTRAIL was detected in several malignant and non-malignant lines, including MCF-7, HCC1937, A375, RA-1, Daudi, and 08398 fibroblasts, but was absent in BT-20, MeWo, WM164, and DG-75. In RA-1 and A375 cancer cells, flow cytometry further confirmed that quercetin treatment increased cell-surface mTRAIL in a concentration-dependent manner, resulting in apoptosis. Collectively, including data from our previously published findings, endogenous mTRAIL expression was detected in 8 of 12 human cancer cell lines (67%) and in all 3 non-transformed cell lines (100%), indicating that expression may vary among cancer cell lines but appears to be consistent in normal cells. Overall, these findings support a role for quercetin in promoting mTRAIL trafficking and presentation at the plasma membrane, ultimately resulting in the demise of neighboring cancer cells. Ongoing studies aim to elucidate the functional significance of endogenous mTRAIL expression across various cell types and to define the molecular mechanism by which quercetin promotes mTRAIL trafficking to the plasma membrane of malignant but not normal cells, with the goal of establishing its potential therapeutic relevance across different cancer types.
利益披露 Disclosure
E. M. Thorpe, None..
C. L. Gladson, None..
M. Kalafatis, None.