用 2-hydroxyoleic acid 靶向 Notch-Furin 轴:胶质母细胞瘤治疗的关键机制。

IF 6.6 2区 医学 Q1 Medicine
Raquel Rodríguez-Lorca, Ramón Román, Roberto Beteta-Göbel, Manuel Torres, Victoria Lladó, Pablo V Escribá, Paula Fernández-García
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引用次数: 0

摘要

目的:胶质母细胞瘤(GBM)是一种高度耐药的侵袭性脑肿瘤。2OHOA 目前正在进行 IIB/III 期临床试验,用于治疗新确诊的 GBM 患者。这种疗法的重点是调节膜的结构和组织,从而调节某些细胞信号,以恢复多种疾病的病理状态。Notch信号与肿瘤发生和细胞存活有关,可能是GBM发病机制的驱动因素。本研究旨在确定 2OHOA 是否调节 Notch 通路,作为其抗肿瘤机制的一部分。通过亚细胞分馏和共聚焦研究分析了Notch受体的处理过程。通过荧光测定评估了Furin在其底物裂解过程中的活性,并通过表面等离子共振测定了其与2OHOA的结合亲和力:结果:我们发现2OHOA通过双重机制抑制Notch2和Notch3信号传导。Notch2的抑制作用是通过物理结合使呋喃活性失活,从而影响其处理过程。相反,Notch3 的转录下调导致该通路的激活降低。此外,我们还发现 HES1 的过表达突出了该通路在 2OHOA 药效中的相关性:这些研究结果表明,2OHOA 对 Notch 信号转导的抑制在其抗肿瘤活性中发挥了作用,这种作用可能是通过直接抑制呋喃来实现的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting the Notch-Furin axis with 2-hydroxyoleic acid: a key mechanism in glioblastoma therapy.

Purpose: Glioblastomas (GBMs) are highly treatment-resistant and aggressive brain tumors. 2OHOA, which is currently running a phase IIB/III clinical trial for newly diagnosed GBM patients, was developed in the context of melitherapy. This therapy focuses on the regulation of the membrane's structure and organization with the consequent modulation of certain cell signals to revert the pathological state in several disorders. Notch signaling has been associated with tumorigenesis and cell survival, potentially driving the pathogenesis of GBM. The current study aims to determine whether 2OHOA modulates the Notch pathway as part of its antitumoral mechanism.

Methods: 2OHOA's effect was evaluated on different components of the pathway by Western blot, Q-PCR, and confocal microscopy. Notch receptor processing was analyzed by subcellular fractionation and colocalization studies. Furin activity was evaluated under cleavage of its substrate by fluorescence assays and its binding affinity to 2OHOA was determined by surface plasmon resonance.

Results: We found that 2OHOA inhibits Notch2 and Notch3 signaling by dual mechanism. Notch2 inhibition is unleashed by impairment of its processing through the inactivation of furin activity by physical association. Instead, Notch3 is transcriptionally downregulated leading to a lower activation of the pathway. Moreover, we also found that HES1 overexpression highlighted the relevance of this pathway in the 2OHOA pharmacological efficacy.

Conclusion: These findings report that the inhibition of Notch signaling by 2OHOA plays a role in its anti-tumoral activity, an effect that may be driven through direct inhibition of furin, characterizing a novel target of this bioactive lipid to treat GBM.

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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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