Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 233, Issue 3, Pages 389-403Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2008.09.016
Keywords
Arsenite/Arsenic; Gene expression profiling; p53; Cell cycle regulation; Apoptosis and oxidative stress
Categories
Funding
- National Institute of Environmental Health Sciences [2-PO1-ES009601, P50 ES012762, P30 ES07033, RO1-ES1063, U10 ES 11387, T32 ES07032]
- US Environmental Protection Agency [RD-83170901]
- University of Washington Royal Research Fund
- Johns Hopkins University Center for Alternatives to Animal Testing (CAAT)
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Arsenic (As) is a well-known environmental toxicant and carcinogen as well as an effective chemotherapeutic agent. The underlying mechanism of this dual capability, however, is not fully understood. Tumor suppressor gene p53, a pivotal cell cycle checkpoint signaling protein, has been hypothesized to play a possible role in mediating As-induced toxicity and therapeutic efficiency. In this Study, we found that arsenite (As3+) induced apoptosis and cell cycle arrest in a dose-dependent manner in both p53(+/+) and p53(-/-) mouse embryonic fibroblasts (MEFs). There was, however, a distinction between genotypes in the apoptotic response, with a more prominent induction of caspase-3 in the p53(-/-) cells than in the p53(+/+) cells. To examine this difference further, a systems-based genomic analysis was conducted comparing the critical molecular mechanisms between the p53 genotypes in response to As3+. A significant alteration in the Nrf2-mediated oxidative stress response pathway was found in both genotypes. In p53(+/+) MEFs, As3+ induced p53-dependent gene expression alterations in DNA damage and cell cycle regulation genes. However, in the p53(-/-) MEFs, As3+ induced a significant up-regulation of pro-apoptotic genes (Noxa) and down-regulation of genes in immune modulation. Our findings demonstrate that AS-induced cell death occurs through a p53-independent pathway in p53 deficient cells while apoptosis induction occurs through p53-dependent pathway in normal tissue. This difference in the mechanism of apoptotic responses between the genotypes provides important information regarding the apparent dichotomy of arsenic's dual mechanisms, and potentially leads to further advancement of its utility as a chemotherapeutic agent. Published by Elsevier Inc.
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