• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

醛酮还原酶1C1（AKR1C1）与信号转导和转录激活因子3（STAT3）相互作用，以增加细胞内谷胱甘肽水平，并赋予结直肠癌对奥沙利铂的抗性。

AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer.

作者信息

Fu Zhiwen, Wu Tingting, Gao Chen, Wang Lulu, Zhang Yu, Shi Chen

机构信息

Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China.

出版信息

Acta Pharm Sin B. 2024 Dec;14(12):5305-5320. doi: 10.1016/j.apsb.2024.08.031. Epub 2024 Sep 2.

DOI:10.1016/j.apsb.2024.08.031
PMID:39807317
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11725136/
Abstract

Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both and . Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.

摘要

奥沙利铂（OXA）是一种铂类化疗药物，仍然是晚期结直肠癌（CRC）一线治疗的主要药物。然而，奥沙利铂耐药性的最终出现是一个重大的临床挑战。在本研究中，我们证明醛糖还原酶1C1（AKR1C1）在获得奥沙利铂耐药性的CRC细胞中过表达，这在奥沙利铂耐药的CRC细胞系中很明显。我们采用基因沉默和药理学抑制策略来确定抑制AKR1C1可恢复奥沙利铂敏感性。机制上，AKR1C1与转录因子STAT3相互作用并激活它，STAT3上调谷氨酸转运体EAAT3，从而提高细胞内谷胱甘肽水平并赋予奥沙利铂耐药性。土木香内酯是一种有效的AKR1C1天然产物抑制剂，可有效逆转这种化疗耐药性，在体内和体外均能抑制奥沙利铂耐药CRC细胞的生长。我们的研究结果揭示了奥沙利铂耐药背后一种关键的依赖AKR1C1的机制，并提出了一种有前景的联合治疗策略来克服CRC中的这种耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/a352dcee2106/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/cd2a7571437c/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/5e1f7c072edb/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/f82bb24e2937/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/a4a4f9e5d21e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/728fd89c0fb8/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/146d6befebee/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/a3030916a4d1/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/78ae9ecbe79a/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/a352dcee2106/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/cd2a7571437c/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/5e1f7c072edb/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/f82bb24e2937/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/a4a4f9e5d21e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/728fd89c0fb8/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/146d6befebee/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/a3030916a4d1/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/78ae9ecbe79a/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3aec/11725136/a352dcee2106/gr8.jpg

相似文献

1
AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer.醛酮还原酶1C1（AKR1C1）与信号转导和转录激活因子3（STAT3）相互作用，以增加细胞内谷胱甘肽水平，并赋予结直肠癌对奥沙利铂的抗性。
Acta Pharm Sin B. 2024 Dec;14(12):5305-5320. doi: 10.1016/j.apsb.2024.08.031. Epub 2024 Sep 2.
2
Suppression MGP inhibits tumor proliferation and reverses oxaliplatin resistance in colorectal cancer.抑制 MGP 可抑制结直肠癌细胞增殖并逆转奥沙利铂耐药性。
Biochem Pharmacol. 2021 Jul;189:114390. doi: 10.1016/j.bcp.2020.114390. Epub 2020 Dec 22.
3
Prostaglandin F synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F-dependent and F-independent mechanism.前列腺素 F 合酶通过前列腺素 F 依赖和非依赖机制促进结直肠癌细胞对奥沙利铂的耐药性。
World J Gastroenterol. 2023 Oct 21;29(39):5452-5470. doi: 10.3748/wjg.v29.i39.5452.
4
Transcription factor B-MYB activates lncRNA CCAT1 and upregulates SOCS3 to promote chemoresistance in colorectal cancer.转录因子B-MYB激活长链非编码RNA CCAT1并上调SOCS3以促进结直肠癌的化疗耐药性。
Chem Biol Interact. 2023 Apr 1;374:110412. doi: 10.1016/j.cbi.2023.110412. Epub 2023 Feb 20.
5
Shikonin potentiates therapeutic efficacy of oxaliplatin through reactive oxygen species-mediated intrinsic apoptosis and endoplasmic reticulum stress in oxaliplatin-resistant colorectal cancer cells.紫草素通过活性氧介导的内在凋亡和内质网应激增强奥沙利铂耐药结直肠癌细胞对奥沙利铂的治疗效果。
Drug Dev Res. 2023 May;84(3):542-555. doi: 10.1002/ddr.22044. Epub 2023 Feb 13.
6
Unraveling the immune landscape and therapeutic biomarker PMEPA1 for oxaliplatin resistance in colorectal cancer: A comprehensive approach.解析结直肠癌奥沙利铂耐药的免疫图谱和治疗性生物标志物 PMEPA1：一种综合方法。
Biochem Pharmacol. 2024 Apr;222:116117. doi: 10.1016/j.bcp.2024.116117. Epub 2024 Mar 8.
7
Gegen Qinlian Decoction reverses oxaliplatin resistance in colorectal cancer by inhibiting YTHDF1-regulated m6A modification of GLS1.秦连解毒汤通过抑制 YTHDF1 调控的 GLS1 的 m6A 修饰逆转结直肠癌细胞对奥沙利铂的耐药性。
Phytomedicine. 2024 Oct;133:155906. doi: 10.1016/j.phymed.2024.155906. Epub 2024 Jul 25.
8
Kruppel-like factor 5 enhances proliferation, lipid droplet formation and oxaliplatin resistance in colorectal cancer by promoting fatty acid binding protein 6 transcription.Kruppel 样因子 5 通过促进脂肪酸结合蛋白 6 的转录增强结直肠癌细胞的增殖、脂滴形成和奥沙利铂耐药性。
Anticancer Drugs. 2023 Nov 1;34(10):1171-1182. doi: 10.1097/CAD.0000000000001515. Epub 2023 Mar 10.
9
Gene expression profiling for analysis acquired oxaliplatin resistant factors in human gastric carcinoma TSGH-S3 cells: the role of IL-6 signaling and Nrf2/AKR1C axis identification.基因表达谱分析鉴定人胃癌 TSGH-S3 细胞获得性奥沙利铂耐药相关因素：IL-6 信号通路和 Nrf2/AKR1C 轴的作用。
Biochem Pharmacol. 2013 Oct 1;86(7):872-87. doi: 10.1016/j.bcp.2013.07.025. Epub 2013 Aug 8.
10
Oxaliplatin resistance in colorectal cancer cells is mediated via activation of ABCG2 to alleviate ER stress induced apoptosis.结直肠癌细胞中的奥沙利铂耐药是通过 ABCG2 的激活来减轻内质网应激诱导的细胞凋亡实现的。
J Cell Physiol. 2018 Jul;233(7):5458-5467. doi: 10.1002/jcp.26406. Epub 2018 Jan 23.

引用本文的文献

1
Targeting the JAK2-STAT3-UCHL3-ENO1 axis suppresses glycolysis and enhances the sensitivity to 5-FU chemotherapy in -mutant colorectal cancer.靶向JAK2-STAT3-UCHL3-ENO1轴可抑制糖酵解并增强 - 突变型结直肠癌对5-氟尿嘧啶化疗的敏感性。
Acta Pharm Sin B. 2025 May;15(5):2529-2544. doi: 10.1016/j.apsb.2025.03.041. Epub 2025 Mar 19.
2
The Role and Mechanism of Innate Immune Regulation in Overcoming Oxaliplatin Resistance and Enhancing Anti-Tumor Efficacy in Colorectal Cancer.天然免疫调节在克服奥沙利铂耐药及增强结直肠癌抗肿瘤疗效中的作用及机制
Pharmaceuticals (Basel). 2025 Feb 24;18(3):317. doi: 10.3390/ph18030317.

本文引用的文献

1
Modulation of redox homeostasis: A strategy to overcome cancer drug resistance.氧化还原稳态的调节：一种克服癌症耐药性的策略。
Front Pharmacol. 2023 Mar 22;14:1156538. doi: 10.3389/fphar.2023.1156538. eCollection 2023.
2
Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers.癌症多药耐药相关分子机制的研究进展
Acta Pharm Sin B. 2023 Mar;13(3):982-997. doi: 10.1016/j.apsb.2022.10.002. Epub 2022 Oct 7.
3
PAFR/Stat3 axis maintains the symbiotic ecosystem between tumor and stroma to facilitate tumor malignancy.
血小板活化因子受体/信号转导与转录激活因子3轴维持肿瘤与基质之间的共生生态系统，以促进肿瘤恶性进展。
Acta Pharm Sin B. 2023 Feb;13(2):694-708. doi: 10.1016/j.apsb.2022.08.014. Epub 2022 Aug 24.
4
A platinum(IV) prodrug strategy to overcome glutathione-based oxaliplatin resistance.一种克服基于谷胱甘肽的奥沙利铂耐药性的铂（IV）前药策略。
Commun Chem. 2022 Apr 6;5(1):46. doi: 10.1038/s42004-022-00661-z.
5
Decreased Levels of GSH Are Associated with Platinum Resistance in High-Grade Serous Ovarian Cancer.谷胱甘肽水平降低与高级别浆液性卵巢癌的铂耐药相关。
Antioxidants (Basel). 2022 Aug 10;11(8):1544. doi: 10.3390/antiox11081544.
6
"Pincer movement": Reversing cisplatin resistance based on simultaneous glutathione depletion and glutathione -transferases inhibition by redox-responsive degradable organosilica hybrid nanoparticles.“钳形运动”：基于氧化还原响应性可降解有机硅杂化纳米颗粒同时消耗谷胱甘肽和抑制谷胱甘肽转移酶来逆转顺铂耐药性
Acta Pharm Sin B. 2022 Apr;12(4):2074-2088. doi: 10.1016/j.apsb.2021.10.013. Epub 2021 Oct 21.
7
Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development.药物代谢与药代动力学科学在药物发现与开发中的翻译研究新进展。
Acta Pharm Sin B. 2022 Jun;12(6):2751-2777. doi: 10.1016/j.apsb.2022.03.009. Epub 2022 Mar 17.
8
Natural Product Alantolactone Targeting AKR1C1 Suppresses Cell Proliferation and Metastasis in Non-Small-Cell Lung Cancer.靶向AKR1C1的天然产物土木香内酯抑制非小细胞肺癌的细胞增殖和转移
Front Pharmacol. 2022 Mar 15;13:847906. doi: 10.3389/fphar.2022.847906. eCollection 2022.
9
Copper-Based Metal-Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically Balanced Cellular Redox Homeostasis.铜基金属有机框架通过系统性破坏动态平衡的细胞氧化还原稳态克服癌症化疗耐药性。
J Am Chem Soc. 2022 Mar 23;144(11):4799-4809. doi: 10.1021/jacs.1c11856. Epub 2022 Feb 22.
10
Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death.转录组谱分析揭示 AKR1C1 和 AKR1C3 通过自噬细胞死亡介导印戒细胞胃癌对顺铂的耐药性。
Int J Mol Sci. 2021 Nov 19;22(22):12512. doi: 10.3390/ijms222212512.