|Table of Contents|

Ginkgetin induces ferroptosis of glioma cells by inhibiting Nrf2/HO-1/GPX4 signaling pathway

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2023 18
Page:
3366-3370
Research Field:
Publishing date:

Info

Title:
Ginkgetin induces ferroptosis of glioma cells by inhibiting Nrf2/HO-1/GPX4 signaling pathway
Author(s):
ZHAO Yinsheng; BAO Long; SUN Tielin; LI Yang
Department of Neurosurgery,the First Affiliated Hospital of Jinzhou Medical University,Liaoning Jinzhou 121000,China.
Keywords:
nuclear factor E2-related factor 2/heme oxygenase-1/glutathione peroxidase 4; Ginkgetin; glioma; ferroptosis
PACS:
R730.264
DOI:
10.3969/j.issn.1672-4992.2023.18.006
Abstract:
Objective:To investigate the impact of Ginkgetin on ferroptosis of glioma cells by inhibiting nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4) signaling pathway.Methods:Human glioma cells U251 were regarded as the research objects,and they were separated into control group,low (Ginkgetin-L,2.5 μmol/L),medium (Ginkgetin-M,5 μmol/L),and high (Ginkgetin-H,10 μmol/L) concentration Ginkgetin group,Nrf2 activator-SFN (sulforaphane,20 μmol SFN) group,and Ginkgetin-H+SFN (10 μmol/L Ginkgetin+20 μmol SFN) group.Flow cytometry,CCK-8,DCFH-DA and Western blot were performed to detect the apoptosis rate,proliferation level,reactive oxygen species (ROS) content and Nrf2/HO-1/GPX4 pathway protein expression level of U251 cells,respectively.Iron ion detection reagent was applied to detect intracellular iron content.Transmission electron microscope was used to observe cell ultrastructure.Results:Compared with the control group,the mitochondrial membrane thickness and ridge changed in Ginkgetin-L,Ginkgetin-M,and Ginkgetin-H groups,the proliferation rate,Nrf2,HO-1,and GPX4 protein expressions decreased obviously,the apoptosis rate,contents of ROS and iron increased obviously (P＜0.05).Compared with the Ginkgetin-H group,the proliferation rate,Nrf2,HO-1,and GPX4 protein expressions increased obviously in Ginkgetin-H+SFN group,the apoptosis rate,contents of ROS and iron decreased obviously (P＜0.05).Compared with the SFN group,the proliferation rate,Nrf2,HO-1,and GPX4 protein expressions decreased obviously in Ginkgetin-H+SFN group,the apoptosis rate,contents of ROS and iron increased obviously (P＜0.05).Conclusion:Ginkgetin can induce ferroptosis in glioma cells by inhibiting the Nrf2/HO-1/GPX4 signaling pathway,thereby exerting an anti-tumor effect.

References:

［1］TAMTAJI OR,BEHNAM M,POURATTAR MA,et al.PIWI-interacting RNAs and PIWI proteins in glioma:molecular pathogenesis and role as biomarkers［J］.Cell Commun Signal,2020,18(1):168.
［2］MORGAN LL.The epidemiology of glioma in adults:a "state of the science" review［J］.Neuro Oncol,2015,17(4):623-624.
［3］LI J,CAO F,YIN HL,et al.Ferroptosis:past,present and future［J］.Cell Death Dis,2020,11(2):88.
［4］黄庆洋,纪东东,田绣云,等.小檗碱通过激活Nrf2-HO-1/GPX4通路抑制小鼠海马神经元HT22细胞的铁死亡［J］.南方医科大学学报,2022,42(6):937-943. HUANG QY,JI DD,TIAN XY,et al.Berberine inhibits erastin-induced ferroptosis of mouse hippocampal neuronal cells possibly by activating the Nrf2-HO-1/GPX4 pathway［J］.Journal of Southern Medical University,2022,42(6):937-943.
［5］HU WH,CHAN GK,DUAN R,et al.Synergy of ginkgetin and resveratrol in suppressing VEGF-induced angiogenesis:a therapy in treating colorectal cancer［J］.Cancers (Basel),2019,11(12):1828.
［6］张申,李晓阳,卫涛涛.银杏叶提取物对胶质瘤细胞NF-κB表达和NO生成的调控［J］.肿瘤防治研究,2006,33(6):397-400,476. ZHANG S,LI XY,WEI TT.Regulatory effect of ginkgo biboba extract on the expression of NF-κB and nitroxide production in glioma cells［J］.Cancer Research on Prevention and Treatment,2006,33(6):397-400,476.
［7］ 焦保华,张晓伟,梁朝辉.银杏叶提取物对大鼠胶质瘤作用机制的体内实验研究［J］.河北医科大学学报,2011,32(1):19-22. JIAO BH,ZHANG XW,LIANG ZH.Anticancer effects of ginkgo biloba extract on brain glioma in rats［J］.Journal of Hebei Medical University,2011,32(1):19-22.
［8］LOU JS,ZHAO LP,HUANG ZH,et al.Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer［J］.Phytomedicine,2021,80:153370.
［9］李无双,周燕,周璇,等.银杏叶提取物对慢性间歇性低氧大鼠胰岛β细胞氧化应激的影响及机制探讨［J］.山东医药,2017,57(30):5-9. LI WS,ZHOU Y,ZHOU X,et al.Effects of ginkgo biloba extracts on oxidative stress of islet β-cells in chronic intermittent hypoxic rats［J］.Shandong Medical Journal,2017,57(30):5-9.
［10］XU H,CHAI SS，LV P,et al.CNN3 in glioma:The prognostic factor and a potential immunotherapeutic target［J］.Medicine (Baltimore),2021,100(46):e27931.
［11］JIAPAER S,FURUTA T,TANAKA S,et al.Potential strategies overcoming the temozolomide resistance for glioblastoma［J］.Neurol Med Chir (Tokyo),2018,58(10):405-421.
［12］LOU JS,BI WC,CHAN GKL,et al.Ginkgetin induces autophagic cell death through p62/SQSTM1-mediated autolysosome formation and redox setting in non-small cell lung cancer［J］.Oncotarget,2017,8(54):93131-93148.
［13］JEON YJ,JUNG SN,YUN J,et al.Ginkgetin inhibits the growth of DU-145 prostate cancer cells through inhibition of signal transducer and activator of transcription 3 activity［J］.Cancer Sci,2015,106(4):413-420.
［14］PARK Y,WOO SH,SEO SK,et al.Ginkgetin induces cell death in breast cancer cells via downregulation of the estrogen receptor［J］.Oncol Lett,2017,14(4):5027-5033.
［15］YE ZN,YU MY,KONG LM,et al.Biflavone ginkgetin,a novel wnt inhibitor,suppresses the growth of medulloblastoma［J］.Nat Prod Bioprospect,2015,5(2):91-97.
［16］PAN J,LI X,GUO F,et al.Ginkgetin attenuates cerebral ischemia-reperfusion induced autophagy and cell death via modulation of the NF-κB/p53 signaling pathway［J］.Biosci Rep,2019,39(9):BSR20191452.
［17］MOU Y,WANG J,WU J,et al.Ferroptosis,a new form of cell death:opportunities and challenges in cancer［J］.J Hematol Oncol,2019,12(1):34.
［18］ ZHANG W,SUN Y,BAI L,et al.RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11［J］.J Clin Invest,2021,131(22):e152067.
［19］GE MH,TIAN H,MAO L,et al.Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway［J］.CNS Neurosci Ther,2021,27(9):1023-1040.
［20］SONG JX,AN JR,CHEN Q,et al.Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice［J］.Bioengineered,2022,13(4):8334-8348.
［21］杨洋,杨梦婷,许潇.醋酸棉酚通过诱导铁死亡抑制脑胶质瘤细胞生长［J］.江苏大学学报:医学版,2022,32(3):246-250. YANG Y,YANG MT,XU X.Inhibitory effect of gossypol acetate on the growth of glioma cells via induction of ferroptosis［J］.Journal of Jiangsu University:Medicine Edition,2022,32(3):246-250.

Memo

Memo:
辽宁省自然科学基金计划项目（编号：2022-BS-313）
Last Update: 1900-01-01