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. Methods and 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 ) 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. Conclusion: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.

Nanoparticles of Titanium and Zinc Oxides as Novel Agents in Tumor Treatment: a Review

“…According to many authors [139, 140, 143, 144], the key role in the cell death induced by the UV-excited NPs of TiO 2 or ZnO is played by ROS. They are strong oxidants but also important agents modulating ROS-sensitive signaling pathways that lead to the cell death.…”

“…Yoo et al [144] studied the ROS mediation in the induction of both intrinsic and extrinsic apoptotic pathways since ROS stimulate the increase of pro-apoptotic protein (Bax) and death ligand (FasL) levels, respectively. ROS induce apoptosis in tumor cells also by modification of the activity of mitogen-activated protein kinases (MAPKs; EC 2.7.11.24) [149] and of the nuclear factor kappa B (NF-κB) [150].…”

Intracellular Signal Modulation by Nanomaterials

“…Authors dissected signaling events leading to similar outcome (apoptosis) and found a significant contribution of chemical composition in downstream signaling events. TiO 2 NPs were shown to induce cell death through ROS dependent extrinsic and intrinsic pathway in human lung fibroblast and breast epithelial cells (Yoo et al, 2012). Moreover, TiO 2 NPs induced cell death in BECs was shown to involve caspase 8/Bid pathway (Kang et al, 2009, Shi et al, 2010).…”

Induction of Cytotoxicity by Selected Nanoparticles in Chinese Hamster Ovary-K1 Cells

“…Likewise, the increased cytotoxicity shown by all nanoparticles in a dosedependent manner may be due to the leakage of cellular enzymes including lactate dehydrogenase through the damaged plasma membrane. Different factors like size, shape and composition of nanoparticles, internalization, metabolism and excretion by the tissue or cell type may account for the differential toxicity of nanoparticles (Yoo et al, 2012;Manke et al, 2013;Sadiq et al, 2015). Further research on particokinetics and cytokinetics is needed to understand the exact mechanism behind nanotoxicity at cellular and genetic level.…”