EGFR-TKIs作用下,pfkfb3依赖的氧化还原稳态和DNA修复支持非小细胞肺癌的细胞存活。

IF 6 3区 医学 Q1 CELL BIOLOGY Cancer & Metabolism Pub Date : 2024-12-18 DOI:10.1186/s40170-024-00366-y
Nadiia Lypova, Susan M Dougherty, Brian F Clem, Jing Feng, Xinmin Yin, Xiang Zhang, Xiaohong Li, Jason A Chesney, Yoannis Imbert-Fernandez
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引用次数: 0

摘要

背景:靶向EGFR的酪氨酸激酶抑制剂(TKIs)的疗效有限,因为耐药细胞群的持续存在,导致治疗耐药。非遗传机制,如代谢重布线,在驱动肺癌细胞进入耐药状态中发挥重要作用,使它们能够在持续的药物治疗下持续存在。方法:本研究采用综合方法研究糖酵解调节因子6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶(PFKFB3)对肺癌细胞对EGFR - TKI治疗的适应性的影响。我们进行了代谢组学研究,以追踪TKI治疗期间PFKFB3抑制对葡萄糖重定向的反应。使用活细胞成像和DCFDA氧化来量化氧化应激水平。采用免疫细胞化学和中性彗星法评估DNA完整性,以响应治疗驱动的氧化应激。结果:我们的代谢谱显示,PFKFB3抑制显著改变了tki处理细胞的代谢谱。它限制了葡萄糖在多元醇途径、糖酵解和TCA循环中的利用,导致ATP水平的消耗。此外,PFKFB3的药理抑制通过降低谷胱甘肽过氧化物酶4 (GPX4)的表达来克服tki驱动的氧化还原能力,从而加剧氧化应激。我们的研究还揭示了PFKFB3通过控制参与碱基切除修复的DNA糖基酶的表达在DNA氧化和损伤中的新作用。因此,抑制PFKFB3通过促进ros依赖性细胞死亡来改善EGFR-TKIs的细胞毒性。结论:我们的研究结果表明,PFKFB3抑制降低了葡萄糖利用和DNA损伤修复,限制了细胞对治疗驱动的氧化应激和DNA完整性损伤的适应性。抑制PFKFB3可能是在EGFR TKI治疗下存活的癌细胞进入耐药状态之前根除它们的有效策略。这些发现可能对开发耐药癌症治疗的新疗法具有潜在的意义。
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PFKFB3-dependent redox homeostasis and DNA repair support cell survival under EGFR-TKIs in non-small cell lung carcinoma.

Background: The efficacy of tyrosine kinase inhibitors (TKIs) targeting the EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment.

Methods: Our study employed a comprehensive approach to examine the impact of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the adaptivity of lung cancer cells to EGFR TKI therapies. We conducted metabolomics to trace glucose rerouting in response to PFKFB3 inhibition during TKI treatment. Live cell imaging and DCFDA oxidation were used to quantify levels of oxidation stress. Immunocytochemistry and Neutral Comet assay were employed to evaluate DNA integrity in response to therapy-driven oxidative stress.

Results: Our metabolic profiling revealed that PFKFB3 inhibition significantly alters the metabolic profile of TKI-treated cells. It limited glucose utilization in the polyol pathway, glycolysis, and TCA cycle, leading to a depletion of ATP levels. Furthermore, pharmacological inhibition of PFKFB3 overcome TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), thereby exacerbating oxidative stress. Our study also unveiled a novel role of PFKFB3 in DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. Consequently, PFKFB3 inhibition improved the cytotoxicity of EGFR-TKIs by facilitating ROS-dependent cell death.

Conclusions: Our results suggest that PFKFB3 inhibition reduces glucose utilization and DNA damage repair, limiting the adaptivity of the cells to therapy-driven oxidative stress and DNA integrity insults. Inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR TKI therapy before they enter the drug-resistant state. These findings may have potential implications in the development of new therapies for drug-resistant cancer treatment.

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来源期刊
自引率
1.70%
发文量
17
审稿时长
14 weeks
期刊介绍: Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.
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