缺氧通过调节细胞氧化还原和基因表达驱动肺癌细胞的可逆细胞周期阻滞。

IF 3.5 4区 医学 Q2 ONCOLOGY
Dharmendra Kumar Maurya, Varshita Mehta, Babita Singh
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引用次数: 0

摘要

缺氧是包括肺癌在内的实体肿瘤的一个公认的临床特征,由于其促进化疗和放疗的耐药作用,与不良预后相关。为了研究缺氧对细胞的影响,我们在1% O2条件下培养A549肺腺癌细胞,观察它们的生长、细胞周期分布和氧化还原状态。缺氧可显著降低细胞增殖,诱导G1期细胞周期阻滞,提示细胞抑制作用。生化分析显示,与正常氧条件相比,缺氧条件下总活性氧和线粒体活性氧(ROS)水平分别增加了2.64倍和2.04倍,同时总硫醇水平也有所升高。为了评估缺氧反应的可逆性,我们进行了一个反向氧暴露实验,将最初在缺氧条件下生长的细胞重新暴露于常氧环境,反之亦然。为了探索潜在的分子机制,我们分析了转录组数据集(GEO加入:GSE48134和GSE42416),发现缺氧下调了参与能量代谢的关键基因(如PDK4, G6PD),细胞周期进程(如CCND1, CDK2)和氧化还原调节(如GCLM, TXNRD1, NQO1, GCLC)。此外,在缺氧和常氧条件下培养24小时的A549细胞中,很少有氧化还原相关基因通过RT-PCR得到验证。重要的是,循环缺氧(间歇性缺氧-再氧化)条件下,一些转录物部分恢复,支持缺氧应激的短暂性,与我们的体外观察结果一致。此外,来自腺癌患者的转录组谱(GEO accession: GSE30979)也与我们的细胞系观察结果相符。因此,我们的研究结果清楚地表明,缺氧导致肺癌细胞暂时的细胞周期停滞,当氧气恢复时,这是可逆的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hypoxia-drives reversible cell cycle arrest in lung cancer cells via modulation of cellular redox and gene expression.

Hypoxia is a well-recognized clinical feature of solid tumors, including lung cancer, and is associated with poor prognosis due to its role in promoting resistance to chemotherapy and radiotherapy. To investigate the cellular consequences of hypoxia, we cultured A549 lung adenocarcinoma cells under 1% O2 and examined their growth, cell cycle distribution, and redox status. Hypoxia significantly reduces cell proliferation and induced G1 phase cell cycle arrest, suggesting a cytostatic effect. Biochemical analysis showed a 2.64- and 2.04-fold increase in total and mitochondrial reactive oxygen species (ROS) levels, respectively, along with an elevated total thiol levels under hypoxic conditions compared to normoxia. To assess the reversibility of the hypoxic response, we performed a reciprocal oxygen exposure experiment where cells initially grown under hypoxia were re-exposed to normoxia, and vice versa. To explore the underlying molecular mechanism, we analyzed transcriptomic datasets (GEO accession: GSE48134 and GSE42416) which revealed that hypoxia downregulated key genes involved in energy metabolism (e.g., PDK4, G6PD), cell cycle progression (e.g., CCND1, CDK2), and redox regulation (e.g., GCLM, TXNRD1, NQO1, GCLC). Further, few of redox-related genes were validated by RT-PCR in A549 cells cultured under hypoxia and normoxia for 24 h. Importantly, cyclic hypoxia (intermittent hypoxia-reoxygenation) conditions showed partial restoration of some of these transcripts, supporting the transient nature of hypoxic stress, consistent with our in vitro observations. Furthermore, transcriptome profiles from adenocarcinoma patients (GEO accession: GSE30979) also match our cell line observations. Thus, our results clearly show that hypoxia causes a temporary cell cycle arrest in lung cancer cells, which is reversible when oxygen is restored.

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来源期刊
Medical Oncology
Medical Oncology 医学-肿瘤学
CiteScore
4.20
自引率
2.90%
发文量
259
审稿时长
1.4 months
期刊介绍: Medical Oncology (MO) communicates the results of clinical and experimental research in oncology and hematology, particularly experimental therapeutics within the fields of immunotherapy and chemotherapy. It also provides state-of-the-art reviews on clinical and experimental therapies. Topics covered include immunobiology, pathogenesis, and treatment of malignant tumors.
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