|Table of Contents|

Targeted inhibition of GOT1-mediated iron death pathway reverses cisplatin resistance in esophageal squamous cell carcinoma cells

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

Issue:
2024 14
Page:
2535-2541
Research Field:
Publishing date:

Info

Title:
Targeted inhibition of GOT1-mediated iron death pathway reverses cisplatin resistance in esophageal squamous cell carcinoma cells
Author(s):
ZHOU Shasha1; GUO Zhiyuan1; QI Weihua1; YANG Chen1; ZHANG Xin2
1.Department 2 of Oncology;2.Department of General Surgery,Handan Central Hospital,Hebei Handan 056001,China.
Keywords:
esophageal squamous cell carcinoma cells; cisplatin; drug resistance; glutamic-oxaloacetic transaminase 1; ferroptosis
PACS:
R735.1
DOI:
10.3969/j.issn.1672-4992.2024.14.007
Abstract:
Objective:To explore whether targeted inhibition of glutamic-oxaloacetic transaminase 1 (GOT1) affects cisplatin (DDP) resistance in esophageal squamous cell carcinoma cells through mediating iron death pathway,and to explore the molecular mechanism.Methods:The survival rate and colony formation number of DDP sensitive cell line Eca-109 and DDP resistant cell line Eca-109/DDP were detected by CCK-8 method and cell colony formation assay.The expression levels of GOT1 in Eca-109 cells and Eca-109/DDP cells were detected by RT-qPCR and Western blot.Eca-109/DDP cells were divided into control group,siNC group,siGOT1 group and siGOT1+Ferrostatin-1 (Fer-1) group.The cell survival rate of each group under different DDP concentrations was detected by CCK-8 method.The number of cell colony formation in each group was detected by cell colony formation experiment.The apoptosis rate in each group was detected by flow cytometry.The level of intracellular reactive oxygen species (ROS) in each group was detected by DCFH-DA staining,and the concentration of iron ion (Fe2+) in each group was detected by colorimetry.The protein expression levels of iron death effector acyl coenzyme A synthetase long chain family member 4 (ACSL4),glutathione peroxidase 4 (GPX4) and solute carrier family member 7 11 (SLC7A11) were detected by Western blot analysis.Results:Compared with Eca-109 cells,the survival rate of Eca-109/DDP cells under different concentrations of DDP was increased (P＜0.05),the number of cell colony formation was increased (P＜0.05),and the relative expression of GOT1 mRNA and protein in the cells was up-regulated (P＜0.05).Compared with the control group,the survival rate of Eca-109/DDP cells in siGOT1 group under different concentrations of DDP was decreased (P＜0.05),the number of cell colony formation was decreased (P＜0.05),the apoptosis rate was increased (P＜0.05),and the ROS level and Fe2+ concentration in cells were increased (P＜0.05),the relative expression of ACSL4 protein was up-regulated (P＜0.05),and the relative expression of GPX4 and SLC7A11 protein was down-regulated (P＜0.05).Compared with siGOT1 group,the survival rate of Eca-109/DDP cells in siGOT1+Fer-1 group under different concentrations of DDP was increased (P＜0.05),the number of cell colony formation was increased (P＜0.05),and the apoptosis rate was decreased (P＜0.05),ROS level and Fe2+ concentration were decreased (P＜0.05),the relative expression of ACSL4 protein was down-regulated and the relative expression of GPX4 and SLC7A11 protein was up-regulated (P＜0.05).Conclusion:Targeted inhibition of GOT1 can enhance the sensitivity of Eca-109/DDP to DDP and promote the apoptosis of the drug-resistant cells,which is related to the promotion of iron death pathway.

References:

[1] YANG T,HUI R,NOUWS J,et al.Untargeted metabolomics analysis of esophageal squamous cell cancer progression［J］.J Transl Med,2022,20(1):127.
[2] NISHIMURA J,DEGUCHI S,TANAKA H,et al.Induction of immunogenic cell death of esophageal squamous cell carcinoma by 5-Fluorouracil and Cisplatin［J］.In Vivo,2021,35(2):743-752.
[3] HIRATA H,NIIDA A,KAKIUCHI N,et al.The evolving genomic landscape of esophageal squamous cell carcinoma under chemoradiotherapy［J］.Cancer Res,2021,81(19):4926-4938.
[4] BIRSOY K,WANG T,CHEN WW,et al.An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis［J］.Cell,2015,162(3):540-551.
[5] LI W,FU H,FANG L,et al.Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy［J］.Front Oncol,2022,12:1025067.
[6] ZHOU X,CURBO S,LI F,et al.Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose［J］.BMC Cancer,2018,18(1):559.
[7] SONG Z,YANG Y,WU Y,et al.Glutamic oxaloacetic transaminase 1 as a potential target in human cancer［J］.Eur J Pharmacol,2022,917:174754.
[8] HONG C,ZHENG J,LI X.Inhibition of GOT1 sensitizes colorectal cancer cells to 5-fluorouracil［J］.Cancer Chemother Pharmacol,2017,79(4):835-840.
[9] GHOSH S.Cisplatin:The first metal based anticancer drug［J］.Bioorg Chem,2019,88:102925.
[10] 周悦思,曲家良,韩英伦.从三羧酸循环代谢异常中探寻癌症进展与治疗新思路［J］.中国细胞生物学学报,2023,45(3):428-435. ZHOU YS,QU JL,HAN YL.Exploring new ideas for cancer progression and treatment from abnormal tricarboxylic acid cycle metabolism［J］.Chinese Journal of Cell Biology,2023,45(3):428-435.
[11] PAVLOVA NN,ZHU J,THOMPSON CB.The hallmarks of cancer metabolism:Still emerging［J］.Cell Metab,2022,34(3):355-377.
[12] PARKER SJ,AMENDOLA CR,HOLLINSHEAD KER,et al.Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer［J］.Cancer Discov,2020,10(7):1018-1037.
[13] GUO Y,CHEN T,LIANG X,et al.Tumor cell derived exosomal GOT1 suppresses tumor cell ferroptosis to accelerate pancreatic cancer progression by activating Nrf2/HO-1 axis via upregulating CCR2 expression［J］.Cells,2022,11(23):3893.
[14] LIU X,SHEN Z.LncRNA TMPO-AS1 aggravates the development of hepatocellular carcinoma via miR-429/GOT1 axis［J］.Am J Med Sci,2020,360(6):711-720.
[15] ZHU X,HAN J,LAN H,et al.A novel circular RNA hsa_circRNA_103809/miR-377-3p/GOT1 pathway regulates cisplatin-resistance in non-small cell lung cancer (NSCLC)［J］.BMC Cancer,2020,20(1):1190.
[16] 马苗,柴克霞.GPx4在铁死亡中的作用及其与疾病相关性的研究进展［J］.中国临床研究,2021,34(5):681-684. MA M,CHAI KX.The role of GPx4 in ferroptosis and its correlation with diseases［J］.Chinese Clinical Research,2021,34(5):681-684.
[17] 程峰,张庸,王祥,等.谷胱甘肽过氧化物酶GPX4在铁死亡中的作用与机制研究进展［J］.现代肿瘤医学，2021,29（7）:1254-1258. CHENG F,ZHANG Y,WANG X,et al.Research progress on the role and mechanism of GPX4 in ferroptosis［J］.Modern Oncology,2021,29（7）:1254-1258.
[18] YUAN H,LI X,ZHANG X,et al.Identification of ACSL4 as a biomarker and contributor of ferroptosis［J］.Biochem Biophys Res Commun,2016,478(3):1338-1343.
[19] KOPPULA P,ZHUANG L,GAN B.Cystine transporter SLC7A11/xCT in cancer:ferroptosis,nutrient dependency,and cancer therapy［J］.Protein Cell,2021,12(8):599-620.
[20] ZHANG C,LIU X,JIN S,et al.Ferroptosis in cancer therapy:a novel approach to reversing drug resistance［J］.Mol Cancer,2022,21(1):47.
[21] WANG Y,WU X,REN Z,et al.Overcoming cancer chemotherapy resistance by the induction of ferroptosis［J］.Drug Resist Updat,2023,66:100916.
[22] 王睿，沙仁高娃.顺铂诱导铁死亡促进肿瘤相关巨噬细胞极化抑制宫颈癌细胞耐药性［J］.现代肿瘤医学，2022,30(13):2320-2325. WANG R,SHARENGAOWA.Cisplatin-induced ferroptosis promotes tumor-associated macrophage polarization to inhibits drug resistance in cervical cancer cells［J］.Modern Oncology,2022,30(13):2320-2325.
[23] KREMER DM,NELSON BS,LIN L,et al.GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis［J］.Nat Commun,2021,12(1):4860.

Memo

Memo:
河北省医学科学研究课题计划（编号：20220449）；河北省邯郸市科学技术研究与发展计划项目（编号：22422083024ZC）
Last Update: 1900-01-01