Lovera-Leroux Melanie, Crobeddu Belinda, Kassis Nadim, Petit Patrice X, Janel Nathalie, Baeza-Squiban Armelle, Andreau Karine
Université Paris Diderot, Sorbonne Paris Cité, Unit of Functional and Adaptive Biology, CNRS UMR 8251, Paris, France.
Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR-S 1124, Paris, France.
Biochimie. 2015 Nov;118:195-206. doi: 10.1016/j.biochi.2015.09.030. Epub 2015 Sep 28.
The classification of outdoor air pollution as carcinogenic for humans strengthens the increasing concern about particulate matter (PM). We previously demonstrated that PM exposure produces an antiapoptotic effect resulting from polycyclic aromatic hydrocarbons (PAH) and water-soluble components. In this study, we investigated transition metallic compounds, particularly iron, in order to decipher their underlying molecular mechanisms that prevent apoptosis. Human bronchial epithelial cells were exposed for 4 h to different PM samples with established antiapoptotic effect (e.g. PM-AW) or not (e.g. PM-VS) or to their metallic components (Fe, Mn, Zn and Al) before apoptosis induction by the calcium ionophore A23187 or Staurosporine. PM-AW, Fe, Mn and Al significantly reduced induced apoptosis. The antiapoptotic effect of Fe was enhanced by benzo(a)pyrene, a typical PAH compound, but was totally reversed by the iron chelator, deferiprone. Furthermore, particles and iron triggered cellular ROS generation and prevented the depletion in glutathione levels observed during A23187-induced apoptosis. In contrast to benzo(a)pyrene, PM-AW and Fe rapidly activated NRF2, subsequently upregulated several target genes (HO1, NQO1 and GPX1) and modulated some genes which control cell death (BCL2, BAX and p53). The key role of the NRF2 pathway in the antiapoptotic effect mediated by Fe and PM was demonstrated using siRNA technology. Our results suggest that the iron component participates in the antiapoptotic effect of PM by activating a NRF2-dependent antioxidant process. As resisting to cell death is one of the hallmarks of cancer cells, these findings provide additional clues for understanding the development of lung cancer after atmospheric pollution exposure.
将室外空气污染归类为对人类致癌，这加剧了人们对颗粒物（PM）日益增长的担忧。我们之前证明，PM暴露会产生由多环芳烃（PAH）和水溶性成分导致的抗凋亡效应。在本研究中，我们研究了过渡金属化合物，特别是铁，以阐明其预防细胞凋亡的潜在分子机制。在通过钙离子载体A23187或星形孢菌素诱导细胞凋亡之前，将人支气管上皮细胞暴露于具有既定抗凋亡效应的不同PM样本（例如PM - AW）或无此效应的样本（例如PM - VS）或其金属成分（铁、锰、锌和铝）4小时。PM - AW、铁、锰和铝显著降低了诱导的细胞凋亡。典型的PAH化合物苯并(a)芘增强了铁的抗凋亡作用，但铁螯合剂去铁酮完全逆转了这种作用。此外，颗粒物和铁引发细胞ROS生成，并防止了A23187诱导的细胞凋亡过程中观察到的谷胱甘肽水平的消耗。与苯并(a)芘不同，PM - AW和铁迅速激活NRF2，随后上调几个靶基因（HO1、NQO1和GPX1）并调节一些控制细胞死亡的基因（BCL2、BAX和p53）。使用siRNA技术证明了NRF2途径在铁和PM介导的抗凋亡作用中的关键作用。我们的结果表明，铁成分通过激活NRF2依赖的抗氧化过程参与PM的抗凋亡作用。由于抵抗细胞死亡是癌细胞的特征之一，这些发现为理解大气污染暴露后肺癌的发生发展提供了额外线索。
