Interactions between SIRT1 and AP-1 reveal a mechanistic insight into the growth promoting properties of alumina (Al2O3) nanoparticles in mouse skin epithelial cells.
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 (Al(2)O(3)/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.
Dey
Swatee
S
Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Health Sciences Research Building 454, Lexington, KY 40536-0298, USA.
Bakthavatchalu
Vasudevan
V
Tseng
Michael T
MT
Wu
Peng
P
Florence
Rebecca L
RL
Grulke
Eric A
EA
Yokel
Robert A
RA
Dhar
Sanjit Kumar
SK
Yang
Hsin-Sheng
HS
Chen
Yumin
Y
St Clair
Daret K
DK
D000537:Aluminum Oxide / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000187:drug effects; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000502:physiology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000502:physiology*; D051020:bcl-X Protein / Q000235:genetics
C494812:Bcl2l1 protein, mouse; D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D051020:bcl-X Protein; D013482:Superoxide Dismutase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D000537:Aluminum Oxide