抑制 SLC7A9 可通过抑制胃癌中的胱氨酸转运诱导铁变态反应,从而增加化疗敏感性。

IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-10-21 DOI:10.1016/j.ebiom.2024.105375
Haoran Feng, Junxian Yu, Zhuoqing Xu, Qingqing Sang, Fangyuan Li, Mengdi Chen, Yunqin Chen, Beiqin Yu, Nan Zhu, Jiazeng Xia, Changyu He, Junyi Hou, Xiongyan Wu, Chao Yan, Zhenggang Zhu, Liping Su, Jianfang Li, Wentao Dai, Yuan-Yuan Li, Bingya Liu
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引用次数: 0

摘要

背景:SLC7A9负责二盐基氨基酸和胱氨酸(流入)与中性氨基酸(流出)的交换。胱氨酸/半胱氨酸转运与铁变态反应有关:方法:桑格测序检测癌细胞的 TP53 状态。转录组测序和非靶向代谢组图谱分析分别用于鉴定 SLC7A9 过表达时的差异表达基因和代谢产物。CCK8、细胞克隆度和EdU测定用于观察细胞增殖。胱氨酸探针、谷胱甘肽(GSH)探针和脂质 ROS 探针用于检测胱氨酸、GSH 和脂质 ROS 水平。13C 代谢流量测定用于监测细胞胱氨酸和 GSH 代谢。利用患者衍生器官组织(PDO)、免疫功能正常的MFC小鼠异种移植模型和患者衍生异种移植(PDX)模型评估SLC7A9对化疗反应的影响,并观察敲除SLC7A9的治疗效果:结果:胃癌细胞中SLC7A9表达水平的升高归因于p53的缺失。SLC7A9敲除抑制了细胞的增殖,并增加了化疗的敏感性。在 PDX 和免疫功能健全的小鼠模型中,SLC7A9 基因敲除后化疗更有效。SLC7A9过表达组和对照组之间表达不同的基因和代谢物与铁变态反应和GSH代谢有关。SLC7A9 基因敲除减少了胱氨酸向细胞内的转运,阻碍了细胞内胱氨酸和 GSH 的代谢流动,减少了 GSH 的合成,并增加了胃癌细胞中脂质 ROS 的水平。SLC7A9被敲除后,Erastin在PDO和PDX模型中诱导铁变态反应的效果更好:SLC7A9通过抑制铁氧化促进胃癌进展,而SLC7A11则受p53负调控:本研究得到了国家自然科学基金、国家健康中心创新推进计划、上海市重点实验室(SIBPT)和上海市科学技术研究院的资助。
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SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via the inhibition of cystine transport in gastric cancer.

Background: SLC7A9 is responsible for the exchange of dibasic amino acids and cystine (influx) for neutral amino acids (efflux). Cystine/cysteine transport is related to ferroptosis.

Methods: Sanger sequencing detected TP53 status of cancer cells. Transcriptomic sequencing and untargeted metabolome profiling were used to identify differentially expressed genes and metabolites, respectively, upon SLC7A9 overexpression. CCK8, cell clonality, and EdU assays were used to observe cell proliferation. Cystine probes, glutathione (GSH) probes, and lipid ROS probes were used to examine cystine, GSH, and lipid ROS levels. 13C metabolic flow assays were used to monitor cellular cystine and GSH metabolism. Patient-derived organoids (PDO), immunocompetent MFC mice allograft models and patient-derived xenograft (PDX) models were used to evaluate SLC7A9 impact on chemotherapeutic response and to observe therapeutic effect of SLC7A9 knockdown.

Findings: Elevated SLC7A9 expression levels in gastric cancer cells were attributed to p53 loss. SLC7A9 knockdown suppressed the proliferation and increased the chemotherapy sensitivity of the cells. Chemotherapy was more effective in PDX and immunocompetent mice models upon SLC7A9 knockdown. Differentially expressed genes and metabolites between the SLC7A9 overexpression and control groups were associated with ferroptosis and GSH metabolism. SLC7A9 knockdown reduced cystine transport into cells, hampered intracellular cystine and GSH metabolic flow, decreased GSH synthesis, and increased lipid ROS levels in gastric cancer cells. Erastin was more effective at inducing ferroptosis in PDO and PDX models upon SLC7A9 knockdown.

Interpretation: SLC7A9 promotes gastric cancer progression by acting as a suppressor of ferroptosis, independent of SLC7A11, which is negatively regulated by p53.

Funding: This work was supported by National Natural Science Foundation of China, Innovation Promotion Program of NHC and Shanghai Key Labs SIBPT, and Shanghai Academy of Science & Technology.

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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