Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells
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 c...
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| Format: | Article |
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MDPI AG
2022-04-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/5/967 |
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| author | Priya Wadgaonkar Zhuoyue Bi Junmei Wan Yao Fu Qian Zhang Bandar Almutairy Wenxuan Zhang Yiran Qiu Chitra Thakur Maik Hüttemann Fei Chen |
| author_facet | Priya Wadgaonkar Zhuoyue Bi Junmei Wan Yao Fu Qian Zhang Bandar Almutairy Wenxuan Zhang Yiran Qiu Chitra Thakur Maik Hüttemann Fei Chen |
| author_sort | Priya Wadgaonkar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T03:18:42Z |
| format | Article |
| id | doaj.art-b5b9decba9d84ce8ad1844f3b87495ea |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T03:18:42Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-b5b9decba9d84ce8ad1844f3b87495ea2023-11-23T10:09:09ZengMDPI AGBiomedicines2227-90592022-04-0110596710.3390/biomedicines10050967Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial CellsPriya Wadgaonkar0Zhuoyue Bi1Junmei Wan2Yao Fu3Qian Zhang4Bandar Almutairy5Wenxuan Zhang6Yiran Qiu7Chitra Thakur8Maik Hüttemann9Fei Chen10Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USAStony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USACenter for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USAStony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USADepartment of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USADepartment of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USAStony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USAStony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USAStony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USACenter for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USADepartment of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USAArsenic 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.https://www.mdpi.com/2227-9059/10/5/967arsenicER stressUPRmetabolismATF6Nrf2 |
| spellingShingle | Priya Wadgaonkar Zhuoyue Bi Junmei Wan Yao Fu Qian Zhang Bandar Almutairy Wenxuan Zhang Yiran Qiu Chitra Thakur Maik Hüttemann Fei Chen Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells Biomedicines arsenic ER stress UPR metabolism ATF6 Nrf2 |
| title | Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells |
| title_full | Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells |
| title_fullStr | Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells |
| title_full_unstemmed | Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells |
| title_short | Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells |
| title_sort | arsenic activates the er stress associated unfolded protein response via the activating transcription factor 6 in human bronchial epithelial cells |
| topic | arsenic ER stress UPR metabolism ATF6 Nrf2 |
| url | https://www.mdpi.com/2227-9059/10/5/967 |
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