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IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC INDUCED BLADDER CANCER BY GENE EXPRESSION.
Citation:
Sen, B., R D. Grindstaff, Y. Turpaz, J. Retief, AND D C. Wolf. IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC INDUCED BLADDER CANCER BY GENE EXPRESSION. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 6-10, 2005.
Description:
Arsenic is a human carcinogen that induces urinary bladder cancer. Several mechanisms have been proposed for arsenic-induced cancer. Although inorganic arsenic (iAs) does not induce tumors in adult rodents, dimethylarsinic acid (DMA), a major metabolite of iAs, is a rat bladder carcinogen. DMA causes a dose-dependent increase in toxicity and induces modulation of genes that control apoptosis, cell proliferation, and the response to oxidative stress in transitional epithelium of the rat urinary bladder. For extrapolation of rat data to human, normal human transitional epithelial cells (Urotsa) were exposed to DMA at 2?M, 20?M, 200?M or 8000?M. Total RNA was isolated and microarray analysis was conducted using the Affymetrix Human U133 Plus 2.0 chips. One way ANOVA identified 1728 genes (p<0.05) out of the 36,967 known genes on the chip. Global expression changes were further characterized using Expression Analysis Systematic Explorer (EASE). In addition to confirming previously described processes, EASE identified additional pathways including phosphorylation, ion transport, protein synthesis and catabolism that were modulated after DMA exposure. Further analysis using Ingenuity Pathway Analysis suggest that altered ERK/MAPK signaling (ERK1/2, CMYC), apoptosis (CASP3, PARP), Wnt-? signaling (WNT, AKT), cell cycle regulation (CYCLIN D, CDKN2A), and PI3K/AKT signaling (FRAP1, HSP90) all play a role in DMA induced cellular toxicity. These pathways are consistent with our previous in vivo studies. This study demonstrated that an in vitro human cell system predicted the same key pathways involved in DMA-induced toxicity as was identified after in vivo exposure in rats.