AB017. NFκB1 regulates FDX1 to facilitate elesclomol-induced cuproptosis against glioblastoma.

IF 2.1 4区医学 Q3 ONCOLOGY

Chinese clinical oncology Pub Date : 2024-08-01 DOI:10.21037/cco-24-ab017

Anyi Wu, Nanheng Yin, Zhipeng Xu, Jun Dong

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引用次数: 0

Abstract

Background: Ferredoxin 1 (FDX1) plays key roles in promoting elesclomol-induced cuproptosis against cancer, whether it has the potential to be a new therapeutic strategy against glioblastoma has not yet been clarified.

Methods: Glioblastoma cells were treated with elesclomol (20 nM/L) and copper chloride (2 μM/L), and then cell proliferation, migration, and invasion were evaluated by CCK-8, clonogenic and transwell assay. Western blot was performed to detect the expression of cuproptosis-relating proteins FDX1, lipoylated dihydrolipoamide S-acetyltransferase (DLAT), copper transport ATPase (ATP7A), heat shock protein 70 (HSP70), apoptotic markers B cell lymphoma-2 (BCL-2) associated X protein (Bax), and BCL-2, as well as the pan-apoptotic/death markers gasdermin D (GSDMD), solute carrier family 7 member 11 (SLC7A11). The effects of knockdown and overexpression of FDX1 on cell proliferation, migration, and invasion were observed. Bioinformatic analysis was performed to predict the corresponding transcription factors regulating FDX1 expression, and verified by dual luciferase assay. The regulatory relationship between FDX1 and its transcription factors was verified by rescue experiment and further evaluated in vivo.

Results: Elesclomol had obvious inhibitory effects on the proliferation, migration, and invasion capacities of tumor cells in a dose-dependent manner. When combined with copper chloride, the inhibitory effects on tumor cells were significantly higher both in vitro and in vivo. FDX1 expression was negatively correlated with overall survival of patients. Nuclear factor κ-light-chain enhancer of activated B cell 1 (NFκB1) was the transcription factor of FDX1 verified by dual luciferase assay. Both FDX1 and NFκB1 were highly expressed in glioblastoma. Knockdown of FDX1 or NFκB1 down-regulated proliferation, migration, and invasion abilities of tumor cells, and increased after FDX1 overexpression. FDX1 expression decreased correspondingly after NFκB1 knockdown. Up-regulation of FDX1 promoted elesclomol-induced cuproptosis against glioblastoma both in vitro and in vivo. FDX1 knockdown can reverse the inhibitory effect of elesclomol on tumor cells.

Conclusions: Elesclomol inhibits glioblastoma development via inducing cuproptosis, regulated by NFκB1/FDX1 axis.

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AB017.NFκB1 可调控 FDX1 以促进伊利克莫尔诱导的杯突症，从而对抗胶质母细胞瘤。

背景：铁雷多辛 1（FDX1）在促进依来克莫尔诱导的杯突症抗癌过程中发挥关键作用，但它是否有可能成为胶质母细胞瘤的一种新的治疗策略尚未明确：方法：用依来克莫尔（20 nM/L）和氯化铜（2 μM/L）处理胶质母细胞瘤细胞，然后用 CCK-8、克隆性和透孔试验评估细胞的增殖、迁移和侵袭。通过 Western 印迹检测杯突相关蛋白 FDX1、脂酰化二氢脂酰胺 S-乙酰转移酶（DLAT）、铜转运 ATPase（ATP7A）、热休克蛋白 70（HSP70）的表达、凋亡标志物 B 细胞淋巴瘤-2（BCL-2）相关 X 蛋白（Bax）和 BCL-2，以及泛凋亡/死亡标志物气体蛋白 D（GSDMD）、溶质运载家族 7 成员 11（SLC7A11）。研究人员观察了敲除和过表达 FDX1 对细胞增殖、迁移和侵袭的影响。生物信息学分析预测了调控FDX1表达的相应转录因子，并通过双荧光素酶实验进行了验证。结果显示，伊利司莫对FDX1有明显的抑制作用：结果：伊利司莫对肿瘤细胞的增殖、迁移和侵袭能力有明显的抑制作用，且呈剂量依赖性。当与氯化铜联合使用时，对肿瘤细胞的抑制作用在体外和体内均明显增强。FDX1 的表达与患者的总生存期呈负相关。通过双荧光素酶试验证实，活化 B 细胞 1 的核因子κ-轻链增强子（NFκB1）是 FDX1 的转录因子。FDX1和NFκB1都在胶质母细胞瘤中高表达。敲除 FDX1 或 NFκB1 会降低肿瘤细胞的增殖、迁移和侵袭能力，而过表达 FDX1 则会增加肿瘤细胞的增殖、迁移和侵袭能力。敲除 NFκB1 后，FDX1 的表达相应减少。在体外和体内，FDX1的上调都能促进依来克莫尔诱导的针对胶质母细胞瘤的杯突症。FDX1敲除可逆转依来氯莫对肿瘤细胞的抑制作用：结论：伊利司莫通过诱导杯突，在NFκB1/FDX1轴的调控下抑制胶质母细胞瘤的发展。

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来源期刊

Chinese clinical oncology ONCOLOGY-

CiteScore

3.90

自引率

0.00%

发文量

期刊介绍： The Chinese Clinical Oncology (Print ISSN 2304-3865; Online ISSN 2304-3873; Chin Clin Oncol; CCO) publishes articles that describe new findings in the field of oncology, and provides current and practical information on diagnosis, prevention and clinical investigations of cancer. Specific areas of interest include, but are not limited to: multimodality therapy, biomarkers, imaging, tumor biology, pathology, chemoprevention, and technical advances related to cancer. The aim of the Journal is to provide a forum for the dissemination of original research articles as well as review articles in all areas related to cancer. It is an international, peer-reviewed journal with a focus on cutting-edge findings in this rapidly changing field. To that end, Chin Clin Oncol is dedicated to translating the latest research developments into best multimodality practice. The journal features a distinguished editorial board, which brings together a team of highly experienced specialists in cancer treatment and research. The diverse experience of the board members allows our editorial panel to lend their expertise to a broad spectrum of cancer subjects.