Arsenic-mediated cellular signal transduction, transcription factor activation, and aberrant gene expression: implications in carcinogenesis.
Arsenic is a common environmental and occupational pollutant and a well-known human carcinogen that causes cancers in many human organs. The exact molecular mechanisms of arsenic carcinogenesis, however, are not well understood. It is generally acknowledged that arsenic does not act via a classic genotoxic or mutagenic mechanism, because it is not a direct mutagen. On the other hand, a growing amount of evidence has shown that arsenic shares many properties with tumor promoters by inducing intracellular signal transduction, activating transcription factors, and changing the expression of genes that are involved in promoting cell growth, proliferation, and malignant transformation. It is postulated that arsenic-induced mitogen-activated protein kinases (MAPKs) signal transduction, which leads to activation of transcription factors such as activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB) (which in turn alter gene expression), is associated with the carcinogenicity of arsenic. In this article, we review the recent findings in arsenic-induced MAPKs, AP-1 and NF-kappaB activation, and aberrant gene expression; their implications in arsenic carcinogenesis are discussed. The elucidation of arsenic-induced signal transduction pathways that lead to aberrant gene expression involved in the arsenic-triggered malignant transformation could help to identify novel molecular targets for the treatment of human cancers resulting from arsenic exposure.
Yang
Chengfeng
C
University of Pennsylvania School of Medicine, Center for Experimental Therapeutics, 421 Curie Blvd, Philadelphia, PA 19104, USA. cfyang@spirit.gcrc.upenn.edu
Frenkel
Krystyna
K
D001151:Arsenic / Q000009:adverse effects*; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D004785:Environmental Pollutants / Q000009:adverse effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology*; D016328:NF-kappa B / Q000494:pharmacology*; D051818:Replication Protein C; D015398:Signal Transduction
D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D016328:NF-kappa B; D020928:Mitogen-Activated Protein Kinases; D051818:Replication Protein C; D001151:Arsenic