Deguelin inhibits the glioblastoma progression through suppressing CCL2/NFκB signaling pathway

IF 4.6 2区 医学 Q1 NEUROSCIENCES Neuropharmacology Pub Date : 2024-08-10 DOI:10.1016/j.neuropharm.2024.110109
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Abstract

Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae Mundulea sericea (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that CCL2 (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB in vivo. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM.

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Deguelin 通过抑制 CCL2/NFκB 信号通路抑制胶质母细胞瘤的进展。
多形性胶质母细胞瘤(GBM)是最常见的原发性颅内肿瘤,具有侵袭性强、预后差的特点。非洲豆科植物Mundulea sericea树皮中的一种成分Deguelin对某些肿瘤具有抗增殖作用,但Deguelin对GBM的抑制作用和机制仍不甚明了。首先,我们发现鹿角菜苷通过使细胞周期停滞在 G2/M 期并诱导细胞凋亡来降低 GBM 细胞的活力。其次,deguelin抑制了GBM细胞的迁移。接着,RNA-seq分析发现,CCL2(编码一种重要的趋化因子CCL2)在deguelin处理的GBM细胞中显著下调。据报道,CCL2通过NFκB信号通路促进GBM细胞的活力和迁移,抑制GBM细胞的凋亡,并调节GBM肿瘤微环境(TME),从而促进GBM的进展。此外,我们还发现CCL2可以挽救deguelin通过NFκB信号通路对GBM细胞的抗抑制作用。最后,我们建立了颅内同种异位 GBM 模型,发现 deguelin 可抑制肿瘤生长,通过抑制 CCL2/NFκB 促进免疫抑制 TME 并抑制体内 GBM 的血管生成。综上所述,这些结果表明,deguelin可通过抑制CCL2/NFκB途径发挥抗GBM作用,这可能为治疗GBM提供了一种新策略。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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