Carcinogenesis Advance Access originally published online on August 1, 2008
Carcinogenesis 2008 29(10):1920-1929; doi:10.1093/carcin/bgn175
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Interactions between SIRT1 and AP-1 reveal a mechanistic insight into the growth promoting properties of alumina (Al2O3) nanoparticles in mouse skin epithelial cells
1 Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Health Sciences Research Building 454, Lexington, KY 40536-0298, USA
2 Department of Pathology, University of Louisville, Louisville, KY 40292, USA
3 Department of Chemical and Materials Engineering, College of Engineering
4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
* To whom correspondence should be addressed. Tel: +1 859 257 3720; Fax: +1 859 323 1059; Email: dstcl00{at}uky.edu
The physicochemical properties of nanomaterials differ from those of the bulk material of the same composition. However, little is known about the underlying effects of these particles in carcinogenesis. The purpose of this study was to determine the mechanisms involved in the carcinogenic properties of nanoparticles using aluminum oxide (Al2O3/alumina) nanoparticles as the prototype. Well-established mouse epithelial JB6 cells, sensitive to neoplastic transformation, were used as the experimental model. We demonstrate that alumina was internalized and maintained its physicochemical composition inside the cells. Alumina increased cell proliferation (53%), proliferating cell nuclear antigen (PCNA) levels, cell viability and growth in soft agar. The level of manganese superoxide dismutase, a key mitochondrial antioxidant enzyme, was elevated, suggesting a redox signaling event. In addition, the levels of reactive oxygen species and the activities of the redox sensitive transcription factor activator protein-1 (AP-1) and a longevity-related protein, sirtuin 1 (SIRT1), were increased. SIRT1 knockdown reduces DNA synthesis, cell viability, PCNA levels, AP-1 transcriptional activity and protein levels of its targets, JunD, c-Jun and BcL-xl, more than controls do. Immunoprecipitation studies revealed that SIRT1 interacts with the AP-1 components c-Jun and JunD but not with c-Fos. The results identify SIRT1 as an AP-1 modulator and suggest a novel mechanism by which alumina nanoparticles may function as a potential carcinogen.
Abbreviations: AP-1, activator protein-1; BrdU, bromodeoxyuridine; DCFH, 2',7'-dichlorofluorescein diacetate; MnSOD, manganese superoxide dismutase; NBT, nitro blue tetrazolium; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; ROS, reactive oxygen species; SiRNA, small interfering RNA; SIRT1, sirtuin 1; TPA, 12-O-tetradecanoylphorbol-13-acetate
These authors contributed equally to this work. Received February 28, 2008; revised July 19, 2008; accepted July 25, 2008.
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