Inhibitor of differentiation 1 (Id1) expression attenuates the degree of TiO2-induced cytotoxicity in H1299 non-small cell lung cancer cells
Introduction
Nanoparticles have industrial applications in many fields, including electronics, biomedical and pharmaceutical sciences, and cosmetics; as well as energy, catalytic, and material applications; and uses in environmental and human health studies (Nowack and Bucheli, 2007, Shelton et al., 2007). Among the metal-based nanoparticles, titanium dioxide (TiO2) is used ubiquitously in everyday life. For example, it can be found in white paint (Maggos et al., 2007), household products (Sul et al., 2002), plastic goods (Bang et al., 2007), medications (Ayon et al., 2006, Caruthers et al., 2007), and orthopedic implants (Piveteau et al., 1999). Regarding the potential of nanoparticles to travel through an organism via inhalation, toxicity studies have indicated that the lungs are the main target organ (Hoet et al., 2004). As the use of TiO2 has increased, concerns about its toxicity in humans and its environmental impact have increased.
A number of lung diseases have already been associated with nanoparticle exposure (Chen et al., 2006). For example, it has been shown that inhaled inorganic particles can induce alveolar inflammation and fibrosis, and can have a pathogenic role in pneumoconiosis and related entities (Thakur et al., 2009). TiO2 particles, especially those in the ultrafine nanometer range, have also been shown to cause lung cancer in rodents (Oberdorster et al., 1992, Qamar et al., 2002, Kiss et al., 2008). Following the administration of particles to animals by inhalation, ultrafine particles were detected in the cytoplasm of all lung cell types in a non-membrane-bound manner, and this finding was verified in cultured cells (Stearns et al., 2001, Takenaka et al., 2006). Other studies have suggested the uptake of TiO2 by alveolar macrophages via macrophage receptor with collagenous structure (MARCO) in an unopsonized manner (Arredouani et al., 2005). From a dermatological point of view, it is of great importance that TiO2 also serves as a physical photoprotective agent and is widely used in cosmetics.
Id1 is a member of the inhibitor of differentiation or DNA-binding (Id) subfamily of bHLH transcription factors (Pesce and Benezra, 1993). Like other subfamily members, Id1 contains a helix-loop-helix (HLH) motif, but not a DNA-binding domain. Therefore, Id1 acts as a dominant negative regulator of other HLH transcription factors by forming inactive heterodimers (Benezra et al., 1990, Qian and Chen, 2008). Multiple lines of evidence suggest that ID1 is an oncogene. ID1 was found to be up-regulated in various human cancers, including breast, prostate, cervical, and ovarian cancers (Lin et al., 2000, Schindl et al., 2001, Schindl et al., 2003, Schoppmann et al., 2003). In addition, increased levels of ID1 expression are correlated with aggressive and high-grade cancer (Coppe et al., 2004, Meteoglu et al., 2008, Yuen et al., 2006). Moreover, it has been shown that the overexpression of ID1 enhances the capacity of cancer cells for proliferation and invasion. Conversely, the knockdown of ID1 inhibits the metastatic potential of breast cancer cells (Fong et al., 2003).
Mitogen-activated protein kinases (MAPKs; ERK1/2, p38MAPK, and JNK/SAPK) are a family of enzymes that transduce signals from the cell membrane to the cell interior in response to a wide range of stimuli, and regulate various cellular biological functions, such as gene expression, mitosis, differentiation, and cell survival/apoptosis (Pearson et al., 2001, Schaeffer and Weber, 1999). Sydlik et al. (2006) showed that treatment with two types of nanoparticles, carbon [nanoparticulate carbon black, (NPCB; Printex 90)] and silica (amorphous SiO2), both with a median diameter of 14 nm, induced proliferation in a rat lung epithelial cell line. Investigating signaling events relevant in that study, they showed that the membrane receptors for epidermal growth factor receptor (EGF-R) and _1-integrin are involved in particle-induced activation of the MAPK ERK1/2 in response to nanoparticle treatment. Although it is known that p38 mitogen-acitvated protein kinase (MAPK) is induced by TiO2 in an immortalized human bronchial epithelial cell line (BEAS 2B cells) (Park et al., 2008), there is relatively little information concerning the role that MAPK signaling occupies in modulating TiO2 nanoparticle-driven cellular responses in lung cancer cells.
In this study, we investigated the cellular influence of TiO2 nanoparticles and the signaling pathway by which TiO2 leads to decrease in cell viability with respect to the role of the MAPK family. In particular, we focused on the induction of apoptotic cell death by TiO2. The decrease in cellular viability by TiO2 was caused by apoptosis. Id1 gene expression decreased, while TiO2 induced apoptosis. Additionally, overexpression of Id1 prevented decrease in cell viability by TiO2, accompanied by the reduction of activation of JNK MAPKs. Data presented in this work show that TiO2 exposure induced a decrease in cell viability by apoptosis, and Id1 is associated with the apoptotic cell death.
Section snippets
Materials and reagents
TiO2 nanopowder (99.9%, Sigma–Aldrich, Product Number 634662, St. Louis, USA), a mixture of anatase and rutile phases, was used without further purification. It is known that TiO2 nanoarticles used in these studies appeared spherical and polydisperse, with a particle diameter ranging from ∼15 to 350 nm, and the particles slightly agglomerated in water and highly agglomerated in RPMI without FBS (Allouni et al., 2009, L’azou et al., 2008). Dimethylsulfoxide (DMSO), penicillin-streptomycin, and
Characterization of TiO2 nanoparticles
TEM (Fig. 1A and B) revealed that the TiO2 nanoparticles in this study were spherical and polygonal in shape with a particle diameter ranging from <11 to <150 nm. The ζ-potential of the nano-TiO2 particles (250 μg/mL) measured in DMEM, was −10.2 ± 1.5 mV at pH 7.4, showing that the surface of TiO2 is negatively charged in cell culture medium (Fig. 1C). The dispersion stability of TiO2 was investigated by inductively coupled plasma atomic emission spectrometry (ICP-AES). Concentrations of TiO2 were
Discussion
Until now, data showing the cytotoxic effects and related mechanism of TiO2 in cultured cells have been inconsistent. In this study, we investigated the cytotoxic effects of TiO2 and the potential mechanism underlying TiO2 toxicity. A few studies have indirectly investigated the toxic effects of TiO2 in vitro, but no clear guidelines are presently available for quantifying the toxicity. Recently, Kiss et al. (2008) reported that TiO2 exerted significant and cell-type dependent effects on
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This work was supported by a 2007 General Project grant from the Ministry of Science and Technology through the International Inhalation Toxicology Evaluation Technology program at the Korea Institute of Toxicology. We are thanks to staffs of KBSI-chuncheon for zeta-potential analysis.
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