ATF3 inhibits arsenic-induced malignant transformation of human bronchial epithelial cells by attenuating inflammation.

Abstract

Arsenic is a naturally occurring metalloid strongly associated with the incidence of lung cancer. Understanding the mechanisms of arsenic-induced carcinogenesis favors the development of effective interventions to reduce the incidence and mortality of lung cancer. In this study, we investigated the role of activating transcription factor 3 (ATF3) in arsenic-induced transformation of human bronchial epithelial cells. ATF3 was upregulated during chronic exposure to 0.25 μM arsenic, and loss of ATF3 promoted arsenic-induced transformation. Moreover, arsenic-transformed ATF3 knockout (ATF3 KO-AsT) cells exhibited more aggressive characteristics, including acceleration in proliferation, resistance to chemotherapy and increase in migratory capacity. RNA-seq revealed that pathways involved in inflammation, cell cycle, EMT and oncogenesis were affected due to ATF3 deficiency during chronic arsenic exposure. Further experiments confirmed the overproduction of IL-6, IL-8 and TNFα as well as enhanced phosphorylation of AKT and STAT3 in ATF3 KO-AsT cells. Our results demonstrate that ATF3 upregulated by chronic low-dose arsenic exposure represses cell transformation and acquisition of malignant characteristics through inhibiting the production of proinflammatory cytokines and activation of downstream proteins AKT and STAT3, providing a new strategy for the prevention of carcinogen-induced lung cancer.

• Authors: Qiwen Shi, Bei Hu, Chen Yang, Shufen Deng, Xiang Cheng, Jing Wu, Nan Qi
• Journal: Toxicology (Toxicology) Vol. 460 Pg. 152890 (08 2021) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 34364923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• ATF3 protein, human
• Activating Transcription Factor 3
• Inflammation Mediators
• Arsenic

Topics

• Activating Transcription Factor 3 (deficiency, genetics)
• Animals
• Arsenic (toxicity)
• Bronchi (metabolism)
• Cell Line, Transformed
• Female
• Gene Knockout Techniques (methods)
• HEK293 Cells
• Humans
• Inflammation Mediators (antagonists & inhibitors, metabolism)
• Lung Neoplasms (chemically induced, metabolism, prevention & control)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Respiratory Mucosa (metabolism)
• Xenograft Model Antitumor Assays (methods)