Oxaliplatin suppresses gastric cancer by inducing cuproptosis

RAO Hang; YANG Hong; XIONG Mengyuan; ZHANG Liyong; HAN Xiao; DENG Boshao; WANG Lulu; CHEN Jian; SHI Yan

doi:10.16016/j.2097-0927.202509094

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Oxaliplatin suppresses gastric cancer by inducing cuproptosis

Basic Medicine | 更新时间：2025-12-30

- Oxaliplatin suppresses gastric cancer by inducing cuproptosis
- Journal of Army Medical University Vol. 47, Issue 24, Pages: 3056-3064(2025)
- 作者机构：
  
  1.陆军军医大学（第三军医大学），第一附属医院（西南医院）普通外科，重庆
  2.陆军军医大学（第三军医大学），基础医学院免疫学教研室，重庆
- 作者简介：
- 基金信息：
- DOI：10.16016/j.2097-0927.202509094
  CLC： R735.2;R966;R979.12
- Received：28 September 2025，
  
  Revised：2025-12-12，
  
  Published：30 December 2025
- 稿件说明：
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饶航，杨虹，熊梦源，等.奥沙利铂通过诱导胃癌细胞铜死亡抑制胃癌［J］.陆军军医大学学报，2025，47（24）：3056-3064.DOI：10.16016/j.2097-0927.202509094.

RAO H，YANG H，XIONG M Y，et al.Oxaliplatin suppresses gastric cancer by inducing cuproptosis［J］.J Army Med Univ，2025，47（24）：3056-3064.DOI：10.16016/j.2097-0927.202509094.
饶航，杨虹，熊梦源，等.奥沙利铂通过诱导胃癌细胞铜死亡抑制胃癌［J］.陆军军医大学学报，2025，47（24）：3056-3064.DOI：10.16016/j.2097-0927.202509094. DOI：

RAO H，YANG H，XIONG M Y，et al.Oxaliplatin suppresses gastric cancer by inducing cuproptosis［J］.J Army Med Univ，2025，47（24）：3056-3064.DOI：10.16016/j.2097-0927.202509094. DOI：

摘要

目的

探索奥沙利铂（oxaliplatin，OXA）治疗胃癌（gastric cancer，GC）时诱导细胞铜死亡（Cuproptosis）能力及潜在机制。

方法

使用UALCAN数据库及Kaplan-Meier绘图仪工具分析铜死亡核心调控蛋白二氢硫辛酰胺S-乙酰转移酶（dihydrolipoamide S-acetyltransferase，DLAT）、铁氧还蛋白1（Ferredoxin 1，FDX1）、硫辛酸合成酶（lipoic acid synthase，LIAS）在胃癌中的表达及预后意义；CCK-8检测奥沙利铂以及联用铜螯合剂四硫代钼酸盐（tetrathiomolybdate，TTM）对MKN-45及BGC-823胃癌细胞的毒性作用；免疫荧光/蛋白质免疫印迹分析铜死亡核心指征蛋白DLAT在线粒体上寡聚化情况及铜死亡调控蛋白FDX1、LIAS的表达；铜离子荧光探针检测OXA及TTM处理后胞内铜离子水平。将5~6周龄SPF级Balb/c nude雌性小鼠（体质量18~25 g）皮下注射胃癌MKN-45细胞建立皮下移植瘤模型，分为（

=4）：对照组（Control组）、奥沙利铂治疗组（OXA组，腹腔注射OXA）及奥沙利铂联用四硫代钼酸盐治疗组（OXA+TTM组，腹腔注射OXA及TTM），定期记录肿瘤大小，绘制肿瘤生长曲线。肿瘤组织经包埋切片后行免疫组化染色检测铜死亡核心调控蛋白（FDX1、LIAS）的表达情况及铜盐染色检测组织内铜离子水平。

结果

胃癌组织中FDX1、DLAT较正常组织表达升高（

0.001），且FDX1、LIAS、DLAT均与胃癌预后相关（

0.001），奥沙利铂抑制MKN-45、BGC-823细胞增殖（24 h IC

为44.89 μmol/L、19.02 μmol/L），奥沙利铂诱导的细胞毒性被铜螯合剂TTM显著拮抗（

0.001）；奥沙利铂诱导DLAT发生显著的线粒体定位寡聚化、胞内铜蓄积及FDX1和LIAS表达下降。动物实验中奥沙利铂单药显著抑制肿瘤生长（

0.01），该效应被四硫代钼酸盐削弱（

0.001）。奥沙利铂单药组肿瘤中FDX1与LIAS蛋白表达水平显著低于对照组及OXA+TTM联合组，以及铜盐染色提示奥沙利铂治疗组可见细胞内铜离子水平明显升高，与体外结果一致。

结论

奥沙利铂可通过诱导胃癌细胞铜死亡抑制胃癌的进展。

Abstract

Objective

To investigate the capacity of oxaliplatin (OXA) in inducing cuproptosis in treatment of gastric cancer and explore the underlying mechanisms.

Methods

Kaplan-Meier Plotter was used to analyze the data in UALCAN database to explore the key regulatory proteins involved in cuproptosis

dihydrolipoamide S-acetyltransferase (DLAT)

ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS) in gastric cancer. The cytotoxic effects of OXA alone and in combination with copper chelator tetrathiomolybdate (TTM) were determined using CCK-8 assays. Immunofluorescence assay and Western blotting were employed to assess the mitochondrial oligomerization of DLAT and the expression levels of FDX1 and LIAS. Intracellular copper levels were measured using a copper-specific fluorescent probe following treatment with OXA and TTM. A subcutaneous tumor model was established through subcutaneous injection of gastric cancer MKN-45 cells in SPF-grade female Balb/c nude mice (5~6 weeks old

weighing 18~25 g). Then the nude mice were randomly assigned into control group

OXA treatment group (intraperitoneal injection)

and OXA and tetrasolybdate (TTM) treatment group. Tumor size was monitored regularly to plot a tumor growth curve. Tumor tissues were harvested

embedded in paraffin

sectioned and then subjected to immunohistochemical (IHC) staining to evaluate expression of FDX1 and LIAS. Copper staining was performed to assess copper levels in tumor tissues.

Results

The expression levels of FDX1 and DLAT were significantly elevated in gastric cancer tissues than normal tissues (

0.001)

and the expression levels of FDX1

DLAT and LIAS were associated with the prognosis of gastric cancer. OXA treatment inhibited cell proliferation in both MKN-45 and BGC-823 cells

with the IC

values of 44.89 and 19.02 μmol/L

respectively. Its cytotoxicity was significantly attenuated by TTM (

0.001). OXA induced pronounced mitochondrial oligomerization of DLAT

intracellular copper accumulation

and reduced FDX1/LIAS expression. In nude mice of transplanted tumor

OXA monotherapy significantly suppresse

d tumor growth (

0.01)

which was weakened by TTM treatment (

0.001)

and decreased the protein levels of FDX1 and LIASr than those in the control and OXA+TTM groups. Copper staining revealed elevated intracellular copper levels in the OXA-treated group

consistent with

in vitro

findings.

Conclusion

OXA inhibits the progression of gastric cancer by inducing cuproptosis in tumor cells.

关键词

Keywords

references

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