title: Titanium dioxide induces apoptotic cell death through reactive oxygen species-mediated Fas upregulation and Bax activation.
abstract: BACKGROUND
  Titanium dioxide (TiO(2)) has been widely used in many areas, including biomedicine, cosmetics, and environmental engineering. Recently, it has become evident that some TiO(2) particles have a considerable cytotoxic effect in normal human cells. However, the molecular basis for the cytotoxicity of TiO(2) has yet to be defined.
  
  
  RESULTS
  In this study, we demonstrated that combined treatment with TiO(2) nanoparticles sized less than 100 nm and ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-dependent upregulation of Fas and conformational activation of Bax in normal human cells. Treatment with P25 TiO(2) nanoparticles with a hydrodynamic size distribution centered around 70 nm (TiO(2) (P25-70)) together with ultraviolet A irradiation-induced caspase-dependent apoptotic cell death, accompanied by transcriptional upregulation of the death receptor, Fas, and conformational activation of Bax. In line with these results, knockdown of either Fas or Bax with specific siRNA significantly inhibited TiO(2)-induced apoptotic cell death. Moreover, inhibition of reactive oxygen species with an antioxidant, N-acetyl-L-cysteine, clearly suppressed upregulation of Fas, conformational activation of Bax, and subsequent apoptotic cell death in response to combination treatment using TiO(2) (P25-70) and ultraviolet A irradiation.
  
  
  CONCLUSIONS
  These results indicate that sub-100 nm sized TiO(2) treatment under ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-mediated upregulation of the death receptor, Fas, and activation of the preapoptotic protein, Bax. Elucidating the molecular mechanisms by which nanosized particles induce activation of cell death signaling pathways would be critical for the development of prevention strategies to minimize the cytotoxicity of nanomaterials.
authors.affiliation: Laboratory of Molecular Biochemistry, Department of Chemistry, Hanyang University, Seoul, Republic of Korea.
authors.forename: Ki-Chun
authors.initials: KC
authors.lastname: Yoo
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Dongwook
authors.initials: D
authors.lastname: Kwon
authors.forename: Kyung-Hwan
authors.initials: KH
authors.lastname: Hyun
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Woo
authors.forename: Rae-Kwon
authors.initials: RK
authors.lastname: Kim
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lim
authors.forename: Yongjoon
authors.initials: Y
authors.lastname: Suh
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Yoon
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010316:Particle Size; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014025:Titanium / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C009495:titanium dioxide; D014025:Titanium; D020169:Caspases