Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells

• Main Authors: Almutairy, B. (Author), Bi, Z. (Author), Chen, F. (Author), Fu, Y. (Author), Hüttemann, M. (Author), Qiu, Y. (Author), Thakur, C. (Author), Wadgaonkar, P. (Author), Wan, J. (Author), Zhang, Q. (Author), Zhang, W. (Author)
• Format: Article
• Language: English
• Published: MDPI 2022
• Subjects: arsenic; ATF6; ER stress; metabolism; Nrf2; UPR
• Online Access: View Fulltext in Publisher

 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 (As3+) 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 As3+ 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 As3+ upregulated both glycolysis and mitochondrial respiration. Analysis of ER UPR signaling pathway using a real-time human UPR array revealed that As3+ 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 As3+ is dose dependent. Chromosome immunoprecipitation and global sequencing indicated a critical role of Nrf2 in mediating As3+-induced expression of these UPR genes. In summary, our data suggest that As3+ is able to regulate the ER stress response, possibly through activating the ATF6 signaling. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.