Abstract

Subchronic exposure to arsenic increases the incidence of human cancers such as skin, lung, colon, and rectal cancer. The mechanism for arsenic-induced tumorigenesis is still not clear. It is generally believed that DNA damage and genomic instability, generated by arsenic-promoted oxidative stress, account largely for this process. The major sources of reactive oxygen species (ROS) are arsenic-damaged mitochondria. Autophagy is a catabolic process functioning in turnover of long-lived proteins and dysfunctional organelles such as mitochondria. Defects of autophagy under stress conditions promote genomic instability and increase the risk of tumorigenesis. In the present study using a human bronchial epithelial cell line, BEAS-2B cells, we investigated the role of autophagy in arsenic-induced cell transformation, an important step in arsenic tumorigenesis. Our results show that subchronic arsenic exposure induces BEAS-2B cell transformation accompanied with increased ROS generation and autophagy activation. However, the patterns for ROS and autophagy alteration are different. Arsenic exposure generated a prolonged and steady increase of ROS levels, whereas the activation of autophagy, after an initial boost by arsenic administration, decreases in response to subchronic arsenic exposure, although the activity is still higher than a nontreated control. Further stimulation of autophagy increases mitochondria turnover and decreases ROS generation and arsenic-induced cell transformation. Contrarily, inhibition of autophagy activity decreases mitochondria turnover and enhances arsenic-induced ROS generation and cell transformation. In addition, the mammalian target of rapamycin signaling pathway is involved in arsenic-mediated autophagy activation. Our results suggest that autophagy is a cell self-protective mechanism against arsenic-induced cell transformation.

Links

Publisher Full Text

Authors

Zhang T, Qi Y, Liao M, Xu M, Bower KA, Frank JA, Shen HM, Luo J, Shi X, Chen G

Institution

Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.

Source

Toxicological sciences : an official journal of the Society of Toxicology 130:2 2012 Dec pg 298-308

MeSH

Animals
Arsenites
Autophagy
Cell Line
Cell Transformation, Neoplastic
Epithelial Cells
Humans
Lung Neoplasms
Male
Mice
Mice, Nude
Microtubule-Associated Proteins
Mitochondria
Oxidative Stress
Protein Kinase Inhibitors
Reactive Oxygen Species
Respiratory Mucosa
Signal Transduction
Sirolimus
Sodium Compounds
TOR Serine-Threonine Kinases
Time Factors
Transfection
Tumor Burden

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22869613