Gao Meili, Zheng Aqun, Chen Lan, Dang Fan, Liu Xiaojing, Gao Jianghong
Department of Biological Science and Engineering, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Department of Preventive Dentistry, Colleague of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Drug Chem Toxicol. 2022 Mar;45(2):741-749. doi: 10.1080/01480545.2020.1774602. Epub 2020 Jun 8.
Benzo(a)pyrene (BaP) is a representative polycyclic aromatic hydrocarbon (PAH) compound, which has been implicated in cancer initiation and promotion. Although BaP is one of the most extensively studied pollutants, the underlying mechanisms through which BaP affects reactive oxygen species (ROS)/hypoxia-inducible factor 1α (HIF-1α)/heme oxygenase 1(HO-1) signaling during lung or breast carcinogenesis are not yet fully understood. In this study, we analyzed the effects of 0 (control), 1, 5, or 25 µM BaP exposure on A549 and MCF-7 cancer cells, by evaluating cell viability, cell cycle, and regulatory protein expression, metabolic gene expression, and ROS/HIF-1α/HO-1 signaling. Cell viability increased following exposure to 1 and 5 µM BaP in A549 cells but decreased following exposure to all concentrations of BaP in MCF-7 cells. BaP significantly increased the proportions of cells in S and G2/M phases, with concomitant reductions in the proportions of cells in G0/G1 phase, following 5 and 25 µM exposure, which was accompanied by the upregulation of the regulatory proteins cyclin A, cyclin B, cyclin-dependent kinase (CDK)1, and CDK2. The subsequent upregulation of cytochrome p450 (CYP)1A1, CYP1B1, CYP3A4, epoxide hydrolase (EH), aldo-keto reductase (AKRC1) expression, and the attenuation of multi-drug resistance protein 4 (MRP4), glutathione-S-transferase (GST)1A1, and GST1B1 were also observed in both cell lines. Moreover, the induction of ROS and the modulation of HIF-1α and HO-1 were observed after BaP exposure. Taken together, these findings suggest that BaP affects proliferation with reference to metabolic genes and ROS/HIF-1α/HO-1 signaling in A549 and MCF-7 cancer cells.
苯并(a)芘（BaP）是一种具有代表性的多环芳烃（PAH）化合物，与癌症的起始和发展有关。尽管BaP是研究最为广泛的污染物之一，但其在肺癌或乳腺癌发生过程中影响活性氧（ROS）/缺氧诱导因子1α（HIF-1α）/血红素加氧酶1（HO-1）信号传导的潜在机制尚未完全明确。在本研究中，我们通过评估细胞活力、细胞周期、调节蛋白表达、代谢基因表达以及ROS/HIF-1α/HO-1信号传导，分析了0（对照）、1、5或25 μM BaP暴露对A549和MCF-7癌细胞的影响。A549细胞暴露于1和5 μM BaP后细胞活力增加，但MCF-7细胞暴露于所有浓度的BaP后细胞活力均下降。在暴露于5和25 μM BaP后，BaP显著增加了处于S期和G2/M期的细胞比例，同时G0/G1期细胞比例相应降低，这伴随着调节蛋白细胞周期蛋白A、细胞周期蛋白B、细胞周期蛋白依赖性激酶（CDK）1和CDK2的上调。随后，在两种细胞系中还观察到细胞色素p450（CYP）1A1、CYP1B1、CYP3A4、环氧化物水解酶（EH）、醛酮还原酶（AKRC1）表达上调，以及多药耐药蛋白4（MRP4）、谷胱甘肽-S-转移酶（GST）1A1和GST1B1表达减弱。此外，BaP暴露后还观察到ROS的诱导以及HIF-1α和HO-1的调节。综上所述，这些发现表明BaP通过影响代谢基因以及A549和MCF-7癌细胞中的ROS/HIF-1α/HO-1信号传导来影响细胞增殖。
