Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells
2022
Priya Wadgaonkar | Zhuoyue Bi | Junmei Wan | Yao Fu | Qian Zhang | Bandar Almutairy | Wenxuan Zhang | Yiran Qiu | Chitra Thakur | Maik Hüttemann | Fei Chen
Arsenic is a well-known human carcinogen associated with a number of cancers, including lung cancers. We have previously shown that long-term exposure to an environmentally relevant concentration of inorganic arsenic (As<sup>3+</sup>) leads to the malignant transformation of the BEAS2B cells, and some of the transformed cells show cancer stem-like features (CSCs) with a significant upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation. In the present report, we investigate the short-term effect of As<sup>3+</sup> on the endoplasmic reticulum (ER) stress response—the “unfolded protein response (UPR)” and metabolism in human bronchial epithelial cell line BEAS-2B cells. Treatment of the cells with inorganic As<sup>3+</sup> upregulated both glycolysis and mitochondrial respiration. Analysis of ER UPR signaling pathway using a real-time human UPR array revealed that As<sup>3+</sup> induced a significant up-regulation of some UPR genes, including ATF6, CEBPB, MAPK10, Hsp70, and UBE2G2. Additional tests confirmed that the induction of ATF6, ATF6B and UBE2G2 mRNAs and/or proteins by As<sup>3+</sup> is dose dependent. Chromosome immunoprecipitation and global sequencing indicated a critical role of Nrf2 in mediating As<sup>3+</sup>-induced expression of these UPR genes. In summary, our data suggest that As<sup>3+</sup> is able to regulate the ER stress response, possibly through activating the ATF6 signaling.
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