AKR1C4 通过调节铁突变调节结直肠癌细胞对化疗的敏感性

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-09-01 Epub Date: 2024-06-18 DOI:10.1007/s00280-024-04685-1
Li Wang, Cuiling Lv, Xiaoxia Liu
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引用次数: 0

摘要

目的:结直肠癌(CRC)仍然是全球关注的主要健康问题,需要创新的治疗策略来提高疗效。本研究探讨了 AKR1C4 在 CRC 中的作用及其对化疗反应的影响:方法:利用CRISPR/Cas9技术生成AKR1C4稳定敲除的CRC细胞系。方法:利用CRISPR/Cas9技术生成了AKR1C4稳定敲除的CRC细胞系,并利用磺基罗丹明B检测法评估了AKR1C4缺失对化疗敏感性的影响。利用浓度不断增加的 5FU、伊立替康和奥沙利铂进行长期低剂量药物诱导,建立获得性化疗耐药的 CRC 细胞系。通过测量总铁含量和脂质过氧化物来检验铁变态反应的诱导和抑制作用:结果:我们发现 AKR1C4 基因敲除能增强 CRC 细胞对化疗的敏感性,特别是通过诱导铁变态反应。AKR1C4的酶活性对调节CRC细胞的化疗敏感性至关重要,Y55A突变体无法逆转化疗敏感性就证明了这一点。此外,AKR1C4抑制剂还能通过诱导铁变态反应提高化疗敏感性。值得注意的是,抑制 AKR1C4 可使获得性化疗耐药的 CRC 细胞对化疗重新敏感,这表明 AKR1C4 有可能成为克服获得性化疗耐药的治疗靶点。临床分析表明,AKR1C4的高表达与接受化疗的CRC患者的不良预后有关,突出了其作为预后标志物和潜在治疗干预靶点的重要性:本研究揭示了 AKR1C4 在 CRC 中的多方面作用,证明了它在调节化疗敏感性、克服获得性耐药和影响临床结果方面的重要性。所提供的见解可能会为治疗 CRC 的新型治疗策略铺平道路。
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AKR1C4 regulates the sensitivity of colorectal cancer cells to chemotherapy through ferroptosis modulation.

Purpose: Colorectal cancer (CRC) remains a major global health concern, necessitating innovative therapeutic strategies to enhance treatment efficacy. In this study, we investigated the role of AKR1C4 in CRC and its impact on chemotherapy response.

Methods: AKR1C4 stable knockout CRC cell lines were generated using CRISPR/Cas9 technology. The impact of AKR1C4 depletion on chemotherapy sensitivity was assessed using Sulforhodamine B assay. Long-term, low-dose drug induction with increasing concentrations of 5FU, irinotecan, and oxaliplatin were employed to establish acquired chemoresistant CRC cell lines. Ferroptosis induction and inhibition were examined through total iron content and lipid peroxidation measurements.

Results: We found that AKR1C4 knockout enhances CRC cell sensitivity to chemotherapy, specifically by inducing ferroptosis. The enzymatic activity of AKR1C4 is crucial for regulating chemotherapy sensitivity in CRC cells, as evidenced by the inability of a Y55A mutant to reverse the sensitizing effect. Additionally, AKR1C4 inhibitors enhance chemotherapy sensitivity by inducing ferroptosis. Notably, AKR1C4 depletion resensitizes the acquired chemoresistant CRC cells to chemotherapy, suggesting its potential as a therapeutic target for overcoming acquired chemoresistance. Clinical analysis reveals that high AKR1C4 expression is associated with poor prognosis in CRC patients undergoing chemotherapy, highlighting its significance as a prognostic marker and a potential target for therapeutic intervention.

Conclusion: This study illuminates the multifaceted role of AKR1C4 in CRC, demonstrating its significance in regulating chemotherapy sensitivity, overcoming acquired resistance, and impacting clinical outcomes. The insights provided may pave the way for novel therapeutic strategies in CRC management.

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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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