Disturbed mitotic progression and genome segregation are involved in cell transformation mediated by nano-TiO2 long-term exposure.
Titanium dioxide (TiO2) nano-particles (<100 nm in diameter) have been of interest in a wide range of applications, such as in cosmetics and pharmaceuticals because of their low toxicity. However, recent studies have shown that TiO2 nano-particles (nano-TiO2) induce cytotoxicity and genotoxicity in various lines of cultured cells as well as tumorigenesis in animal models. The biological roles of nano-TiO2 are shown to be controversial and no comprehensive study paradigm has been developed to investigate their molecular mechanisms. In this study, we showed that short-term exposure to nano-TiO2 enhanced cell proliferation, survival, ERK signaling activation and ROS production in cultured fibroblast cells. Moreover, long-term exposure to nano-TiO2 not only increased cell survival and growth on soft agar but also the numbers of multinucleated cells and micronucleus (MN) as suggested in confocal microscopy analysis. Cell cycle phase analysis showed G2/M delay and slower cell division in long-term exposed cells. Most importantly, long-term TiO2 exposure remarkably affected mitotic progression at anaphase and telophase leading to aberrant multipolar spindles and chromatin alignment/segregation. Moreover, PLK1 was demonstrated as the target for nano-TiO2 in the regulation of mitotic progression and exit. Notably, a higher fraction of sub-G1 phase population appeared in TiO2-exposed cells after releasing from G2/M synchronization. Our results demonstrate that long-term exposure to nano-TiO2 disturbs cell cycle progression and duplicated genome segregation, leading to chromosomal instability and cell transformation.
Huang
Shing
S
Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 402, Taiwan.
Chueh
Pin Ju
PJ
Lin
Yun-Wei
YW
Shih
Tung-Sheng
TS
Chuang
Show-Mei
SM
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000473:pathology; D020090:Chromosome Segregation; D003603:Cytotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D041681:NIH 3T3 Cells; D053758:Nanoparticles; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014025:Titanium / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D003603:Cytotoxins; D048049:Extracellular Signal-Regulated MAP Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D014025:Titanium; D000097869:Polo-Like Kinase 1; C009495:titanium dioxide