Organophosphate‐pesticides induced survival mechanisms and APE1‐mediated Nrf2 regulation in non‐small‐cell lung cancer cells,Journal of Biochemical and Molecular Toxicology

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Organophosphate‐pesticides induced survival mechanisms and APE1‐mediated Nrf2 regulation in non‐small‐cell lung cancer cells
Journal of Biochemical and Molecular Toxicology ( IF 3.2 ) Pub Date : 2020-10-20 , DOI: 10.1002/jbt.22640
Shweta Thakur _{1,

2} , Bibekananda Sarkar _{1,

3} , Monisha Dhiman ₄ , Anil K Mantha ₁

Affiliation

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.

更新日期：2020-10-20

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