Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells
Priya Wadgaonkar,
Zhuoyue Bi,
Junmei Wan,
Yao Fu,
Qian Zhang,
Bandar Almutairy,
Wenxuan Zhang,
Yiran Qiu,
Chitra Thakur,
Maik Hüttemann,
Fei Chen
Affiliations
Priya Wadgaonkar
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
Zhuoyue Bi
Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USA
Junmei Wan
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USA
Yao Fu
Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USA
Qian Zhang
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
Bandar Almutairy
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
Wenxuan Zhang
Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USA
Yiran Qiu
Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USA
Chitra Thakur
Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USA
Maik Hüttemann
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USA
Fei Chen
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
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.
