Carcinogenesis Advance Access published online on August 1, 2008
Carcinogenesis, 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, Lexington, KY 40536, USA
2 College of Engineering, University of Kentucky, Lexington, KY 40536, USA
3 College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
4 Department of Pathology, University of Louisville, Louisville, KY 40292, USA
** Author to whom correspondence should be addressed: Daret K. St.Clair, PhD, Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, HSRB 454, Lexington, KY 40536-0298, Phone: 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%), proliferative cell nuclear antigen (PCNA) levels, cell viability, and growth in soft agar. The level of manganese superoxide dismutase (MnSOD), a key mitochondrial-antioxidant enzyme, was elevated, suggesting a redox signaling event. In addition, the levels of reactive oxygen species (ROS) and the activities of the redox sensitive transcription factor AP-1 and a longevity-related protein, (sirtuin-1) SIRT1, were increased. SIRT1 knock-down reduces DNA synthesis, cell viability, PCNA levels, AP-1 transcriptional activity, and protein levels of its targets, JunD, cJun, and BcLxl, more than controls do. Immunoprecipitation studies revealed that SIRT1 interacts with the AP-1 components cJun and JunD, but not with cFos. The results identify SIRT1 as an AP-1 modulator and suggest a novel mechanism by which alumina nanoparticles may function as a potential carcinogen.
Key Words: nanoparticle • oxidative stress • SIRT 1 • AP1
* These authors contributed equally to this manuscript.
Received February 28, 2008; revised July 19, 2008; accepted July 25, 2008.
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