Department of Zoology, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India.
Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, Odisha, India.
J Biochem Mol Toxicol. 2021 Feb;35(2):e22640. doi: 10.1002/jbt.22640. Epub 2020 Oct 20.
Epidemiological and molecular studies have indicated that environmental exposure to organophosphate pesticides (OPPs) is associated with increased cancer risk; however, the underlying molecular mechanisms still need to be explained. Increasing cancer incidence is linked to OPPs-induced oxidative stress (OS). Our study evaluates monocrotophos (MCP) and chlorpyrifos (CP)-induced OS responses and apurinic/apyrimidinic endonuclease 1 (APE1) role in human non-small-cell lung cancer (NSCLC) cells. Our prior study has implicated OPPs-induced base excision repair (BER)-pathway dysregulation and APE1-mediated regulation of transcription factor (TF) c-jun in A549 cells. We further investigated the effects of MCP and CP on apoptosis, proliferation, and APE1's redox-regulation of nuclear factor-like 2 (Nrf2). Data demonstrates that MCP and CP at subtoxic concentrations induced reactive oxygen species generation and oxidative DNA base damage 8-oxo-dG lesions in NCI-H1299 cells. CP moderately upregulated the apoptosis-inducing factor (AIF) in A549 cells, however, it did not trigger other pro-apoptotic factors viz. caspase-9 and caspase-3, suggesting early caspase-independent apoptosis. However, dose-dependent AIF-downregulation was observed for MCP treatment. Furthermore, CP and MCP treatments upregulated proliferating cell nuclear antigen levels. Immunofluorescent confocal imaging showed the colocalization of APE1 with Nrf2 in 10 µM CP- and MCP-treated NCI-H1299 cells. Immunoprecipitation confirmed that APE1 and Nrf2 physically interacted, indicating the role of APE1-mediated Nrf2 activation following OPPs treatment. This study suggests that low concentration MCP and CP exposure generates OS along with DNA damage, and modulates apoptosis, and APE1-mediated Nrf2 activation, which might be considered as the possible mechanism promoting lung cancer cell survival, suggesting that APE1 may have the potential to become a therapeutic target for the treatment of NSCLC.
流行病学和分子研究表明，接触有机磷农药（OPPs）与癌症风险增加有关；然而，其潜在的分子机制仍有待解释。癌症发病率的增加与 OPPs 诱导的氧化应激（OS）有关。我们的研究评估了久效磷（MCP）和毒死蜱（CP）诱导的 OS 反应以及脱嘌呤/脱嘧啶内切酶 1（APE1）在人非小细胞肺癌（NSCLC）细胞中的作用。我们之前的研究表明，OPPs 诱导的碱基切除修复（BER）途径失调以及 APE1 介导的转录因子（TF）c-jun 调节在 A549 细胞中起作用。我们进一步研究了 MCP 和 CP 对凋亡、增殖以及 APE1 对核因子样 2（Nrf2）的氧化还原调节的影响。数据表明，MCP 和 CP 在亚毒性浓度下诱导了 NCI-H1299 细胞中活性氧的产生和氧化 DNA 碱基损伤 8-氧代-dG 损伤。CP 适度地上调了 A549 细胞中的凋亡诱导因子（AIF），但没有触发其他促凋亡因子，如 caspase-9 和 caspase-3，表明早期 caspase 非依赖性凋亡。然而，在 MCP 处理中观察到 AIF 的剂量依赖性下调。此外，CP 和 MCP 处理上调了增殖细胞核抗原水平。免疫荧光共聚焦成像显示，在 10 μM CP 和 MCP 处理的 NCI-H1299 细胞中，APE1 与 Nrf2 共定位。免疫沉淀证实 APE1 和 Nrf2 物理相互作用，表明 OPPs 处理后 APE1 介导的 Nrf2 激活作用。这项研究表明，低浓度的 MCP 和 CP 暴露会产生 OS 以及 DNA 损伤，并调节凋亡和 APE1 介导的 Nrf2 激活，这可能被认为是促进肺癌细胞存活的可能机制，表明 APE1 可能成为治疗 NSCLC 的潜在治疗靶点。
