RFC3基因敲低可通过诱导铁凋亡增强结肠癌细胞对奥沙利铂的敏感性。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2025-02-01 DOI:10.1111/fcp.13044

Youyi Wu, Tingting Chen, Songsong Wu, Yiwei Huang, Fuyao Li

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引用次数: 0

摘要

背景：对奥沙利铂耐药的发展是一个多方面的过程，通常涉及药物转运、DNA修复机制的改变以及细胞逃避药物诱导的凋亡的能力。目的：评估敲除RFC3是否促进结直肠癌（CRC）细胞对奥沙利铂的敏感性，可能为对抗耐药提供新的途径。方法：在结直肠癌细胞系中采用sirna介导的RFC3敲低来评估对奥沙利铂反应性的影响。通过细胞活力测定、克隆存活测定和流式细胞术评估其对细胞生长和凋亡的影响。此外，使用免疫印迹分析来仔细检查Wnt/β-catenin/GPX4轴上关键蛋白表达的表达变化。结果：RFC3在结直肠癌组织中高表达，且与预后相关。敲除RFC3可增强CRC细胞对奥沙利铂的敏感性。此外，RFC3的减少通过诱导铁下垂促进化疗耐药肿瘤细胞对奥沙利铂的易感性。此外，RFC3的敲低会破坏Wnt/β-catenin/GPX4轴。结论：RFC3缺失通过诱导铁凋亡增强CRC细胞对奥沙利铂的敏感性。

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Knockdown of RFC3 enhances the sensitivity of colon cancer cells to oxaliplatin by inducing ferroptosis.

Background: The development of resistance to oxaliplatin is a multifaceted process, often involving modifications in drug transport, DNA repair mechanisms, and the ability of cells to evade drug-induced apoptosis.

Objective: To evaluate whether knocking down RFC3 promotes the sensitivity of colorectal cancer (CRC) cells to oxaliplatin, potentially offering a new approach to combat drug resistance.

Methods: siRNA-mediated knockdown of RFC3 was employed in colorectal cancer cell lines to assess the impact on oxaliplatin responsiveness. Cell viability assays, clonogenic survival assays, and flow cytometry were conducted to evaluate the effects on cell growth and apoptosis. Additionally, immunoblot analysis was used to scrutinize modifications in the expression of pivotal protein expression in the Wnt/β-catenin/GPX4 axis.

Results: RFC3 is highly expressed in CRC tissues and associated with prognosis. Knocking down RFC3 enhances the sensitivity of CRC cells to oxaliplatin. Additionally, the reduction of RFC3 promotes the susceptibility of chemoresistant tumor cells to oxaliplatin by inducing ferroptosis. Furthermore, the knockdown of RFC3 disrupts the Wnt/β-catenin/GPX4 axis.

Conclusion: Depletion of RFC3 enhances the sensitivity of CRC cells to oxaliplatin via inducing ferroptosis.

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.