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Carcinogenesis Advance Access published online on September 26, 2003
Carcinogenesis, doi:10.1093/carcin/bgg179
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CANCER BIOLOGY

Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells

Andy T. Y. Lau 1, Muyao Li 2, Ronglin Xie 3, Qing-Yu He 4, and Jen-Fu Chiu 1*

1 Institute of Molecular Biology and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
2 Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405
3 Department of Cell Biology, University of Massachusetts Medical Center, Worcester, MA 01655, USA
4 Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, and Department of Chemistry, The University of Hong Kong, Hong Kong SAR, China

* Corresponding author. E-mail: jfchiu{at}hkucc.hku.hk.

Received 15 March 2003 ; revised 16 August 2003 ; accepted 12 September 2003

Abstract

Arsenic is a well-known carcinogen that possibly promotes tumors and the development of various types of cancer in individuals chronically exposed to arsenic in their work or living environment. Many studies have demonstrated the activation of MAPKs in several cell types by using lethal concentrations of arsenic in the range of 50-500 µM. Since the exposure of humans to arsenic is normally at a much lower level in the workplace or in daily life, it is more relevant to study the effects of arsenic at this lower exposure level. In the present study we aimed at re-defining the role of signal transduction pathways in arsenic-induced malignant transformation as well as apoptosis using our established in vitro rat lung epithelial cell model system. Our results indicate a molecular mechanism by which MAPK pathways might differentially contribute to cell growth regulation and cell death in response to different dosages of arsenite. A low level (2 µM) of arsenite stimulated ERK signaling pathway and enhanced cell proliferation, and this arsenite-induced ERK activity was blocked by MEK inhibitor, PD98059. In contrast, a high level (40 µM) of arsenite stimulated the JNK signaling pathway and induced cell apoptosis, and this arsenite-induced JNK activity was blocked by JNK inhibitor II, SP600125. The implications of these findings are that a high concentration of arsenic exposure causes apoptosis, whereas a low concentration of arsenic exposure is carcinogenic and may result in aberrant cell accumulation.


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