Furanodienone overcomes temozolomide resistance in glioblastoma through the downregulation of CSPG4-Akt-ERK signalling by inhibiting EGR1-dependent transcription
Furanodienone overcomes temozolomide resistance in glioblastoma through the downregulation of CSPG4-Akt-ERK signalling by inhibiting EGR1-dependent transcription
复制标题
呋喃二烯酮通过抑制 EGR1 依赖性转录，下调 CSPG4-Akt-ERK 信号传导，克服胶质母细胞瘤中的替莫唑胺耐药性
DOI：
10.1002/ptr.6363
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发表时间：
2019-06-01
影响因子：
7.2
通讯作者：
Li, Wei-ping
中科院分区：
文献类型：
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作者：
Chen, Lei;Liu, Yue-cheng;Li, Wei-ping
多形性胶质母细胞瘤（GBM）是一种高度侵袭性的脑肿瘤。GBM患者对化疗反应差，生存结局差。神经胶质细胞抗原2（NG 2），也称为硫酸软骨素蛋白聚糖4（CSPG 4），已被证明有助于关键过程，如细胞存活，增殖和化疗耐药性，在胶质瘤的进展。在这项研究中，我们发现，呋喃二烯酮（FUR），从莪术根茎中分离的二烯型倍半萜烯，表现出潜在的细胞毒性作用的替莫唑胺（TMZ）耐药GBM细胞在体外抑制CSPG 4和相关的信号通路。研究其机制的研究表明，FUR抑制CSPG 4-Akt-ERK信号传导、炎症反应和细胞因子水平，但激活半胱天冬酶依赖性途径和线粒体功能障碍。此外，免疫荧光测定和双荧光素酶报告基因测定显示，抑制EGFR 1介导的转录可能有助于FUR依赖性阻断CSPG 4信号传导和胶质瘤细胞存活。这些结果建立了FUR诱导的CSPG 4抑制和EGR 1依赖性转录抑制之间的联系。ERK 1/2和细胞因子信号转导的减弱可能在FUR诱导的细胞凋亡过程中产生了CSPG 4通路的EGR 1依赖性负反馈环。这些发现表明，FUR可能是通过靶向CSPG 4信号转导治疗恶性胶质瘤的治疗候选物。
Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumour. Patients with GBM respond poorly to chemotherapy and have poor survival outcomes. Neuron-glial antigen 2 (NG2), also known as chondroitin sulphate proteoglycan 4 (CSPG4), has been shown to contribute to critical processes, such as cell survival, proliferation, and chemotherapy resistance, during glioma progression. In this study, we found that furanodienone (FUR), a diene-type sesquiterpene isolated from the rhizomes of Rhizoma curcumae, exhibited a potential cytotoxic effect on temozolomide (TMZ)-resistant GBM cells in vitro by inhibiting CSPG4 and related signalling pathways. Studies investigating the mechanism demonstrated that FUR suppressed CSPG4-Akt-ERK signalling, inflammatory responses, and cytokine levels but activated caspase-dependent pathways and mitochondrial dysfunction. Furthermore, an immunofluorescence assay and a dual-luciferase reporter assay revealed that inhibition of EGR1-mediated transcription might have contributed to the FUR-dependent blockade of CSPG4 signalling and glioma cell survival. These results established a link between FUR-induced CSPG4 inhibition and the suppression of EGR1-dependent transcription. Attenuation of ERK1/2 and cytokine signalling might have generated the EGR1-dependent negative feedback loop of the CSPG4 pathway during FUR-induced apoptosis. These findings suggested that FUR could be a therapeutic candidate for the treatment of malignant glioma via targeting CSPG4 signalling.