4,5-Dimethoxycanthin-6-one Inhibits Glioblastoma Stem Cell and Tumor Growth by Inhibiting TSPAN1 Interaction with TM4SF1

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemical Research Pub Date : 2024-07-26 DOI:10.1007/s11064-024-04211-y

Wei Li, Li-jian Yang, Yuan-yuan Xiong, Zeng-shi Li, Xi Li, Yi Wen

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Abstract

Glioblastoma stem cells (GSCs) have been implicated in the self-renewal and treatment resistance of glioblastoma (GBM). Our previous study found that 4,5-dimethoxycanthin-6-one has the potential to inhibit GBM cell proliferation. This current study aims to elucidate the molecular mechanism underlying the effects of 4,5-dimethoxycanthin-6-one in GBM development. The effect of 4,5-dimethoxycanthin-6-one on GSC formation and differentiation was explored in human GBM cell lines U251 and U87. Subsequently, 4,5-dimethoxycanthin-6-one binding to tetraspanin 1 (TSPAN1) / transmembrane 4 L six family member 1 (TM4SF1) was analyzed by molecular simulation docking. Co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were used to assess the interactions between TSPAN1 and TM4SF1 in GSCs. Cell proliferation was detected by cell counting kit-8 (CCK-8) and colony formation assay. To evaluate cell migration, invasion and apoptosis, we employed wound healing assay, transwell and flow cytometry, respectively. Furthermore, subcutaneous xenograft tumor models in nude mice were constructed to evaluate the impact of 4,5-dimethoxycanthin-6-one on GSCs in vivo by examining tumor growth and histological characteristics. 4,5-Dimethoxycanthin-6-one inhibited GSC formation and promoted stem cell differentiation in a concentration-dependent manner. Molecular docking models of 4,5-dimethoxycanthin-6-one with TM4SF1 and TSPAN1 were constructed. Then, the interaction between TSPAN1 and TM4SF1 in GSC was clarified. Moreover, 4,5-dimethoxycanthin-6-one significantly inhibited the expressions of TM4SF1 and TSPAN1 in vitro and in vivo. Overexpression of TSPAN1 partially reversed the inhibitory effects of 4,5-dimethoxycanthin-6-one on GSC formation, proliferation, migration and invasion. 4,5-Dimethoxycanthin-6-one inhibited GBM progression by inhibiting TSPAN1/TM4SF1 axis. 4,5-Dimethoxycanthin-6-one might be a novel and effective drug for the treatment of GBM.

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4,5-二甲氧基黄嘌呤-6-酮通过抑制 TSPAN1 与 TM4SF1 的相互作用抑制胶质母细胞瘤干细胞和肿瘤生长

胶质母细胞瘤干细胞（GSCs）与胶质母细胞瘤（GBM）的自我更新和耐药性有关。我们之前的研究发现，4,5-二甲氧基黄嘌呤-6-酮具有抑制 GBM 细胞增殖的潜力。本研究旨在阐明 4,5-二甲氧基黄嘌呤-6-酮在 GBM 生长过程中的分子机制。研究人员在人类 GBM 细胞系 U251 和 U87 中探讨了 4,5-二甲氧基黄嘌呤-6-酮对 GSC 形成和分化的影响。随后，通过分子模拟对接分析了4,5-二甲氧基黄嘌呤-6-酮与四跨蛋白1（TSPAN1）/跨膜4 L六家族成员1（TM4SF1）的结合。共免疫沉淀（Co-IP）和免疫荧光（IF）用于评估 TSPAN1 和 TM4SF1 在 GSCs 中的相互作用。通过细胞计数试剂盒-8（CCK-8）和集落形成试验检测细胞增殖。为了评估细胞迁移、侵袭和凋亡，我们分别采用了伤口愈合试验、透孔法和流式细胞术。此外，我们还构建了裸鼠皮下异种移植肿瘤模型，通过检测肿瘤生长和组织学特征来评估 4,5-二甲氧基黄嘌呤-6-酮对体内 GSCs 的影响。4,5-二甲氧基黄嘌呤-6-酮以浓度依赖的方式抑制了GSC的形成并促进了干细胞的分化。研究人员构建了4,5-二甲氧基黄嘌呤-6-酮与TM4SF1和TSPAN1的分子对接模型。然后，阐明了TSPAN1和TM4SF1在GSC中的相互作用。此外，4,5-二甲氧基黄嘌呤-6-酮能显著抑制TM4SF1和TSPAN1在体外和体内的表达。过量表达TSPAN1可部分逆转4,5-二甲氧基黄嘌呤-6-酮对GSC形成、增殖、迁移和侵袭的抑制作用。4,5-二甲氧基黄嘌呤-6-酮通过抑制 TSPAN1/TM4SF1 轴来抑制 GBM 的进展。4,5-二甲氧基黄嘌呤-6-酮可能是一种治疗GBM的新型有效药物。

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来源期刊

Neurochemical Research 医学-神经科学

CiteScore

7.70

自引率

2.30%

发文量

320

审稿时长

6 months

期刊介绍： Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.