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Article

ZnO Nanoparticles Induced Caspase-Dependent Apoptosis in Gingival Squamous Cell Carcinoma through Mitochondrial Dysfunction and p70S6K Signaling Pathway

1
Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan
2
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
3
Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
4
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
5
Department of Water Resources and Environmental Engineering, Tamkang University, New Taipei City 251, Taiwan
6
Department of Nursing, MacKay Medical College, New Taipei City 252, Taiwan
7
Department of Medical Research, MacKay Memorial Hospital, Taipei 104, Taiwan
8
MacKay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan
9
Department of Radiation Oncology, MacKay Memorial Hospital, Taipei 104, Taiwan
10
Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan
11
Department of Orthopaedics, MacKay Memorial Hospital, Taipei 104, Taiwan
12
Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu 300, Taiwan
13
General Education Center, University of Taipei, Taipei 100, Taiwan
14
Division of General Surgery, Taipei City Hospital, Taipei 103, Taiwan
15
Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County 350, Taiwan
16
Institute of Geriatric Welfare Technology and Science, MacKay Medical College, New Taipei City 252, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(5), 1612; https://doi.org/10.3390/ijms21051612
Received: 16 December 2019 / Revised: 7 February 2020 / Accepted: 20 February 2020 / Published: 26 February 2020
(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)
Zinc oxide nanoparticles (ZnO-NPs) are increasingly used in sunscreens, food additives, pigments, rubber manufacture, and electronic materials. Several studies have shown that ZnO-NPs inhibit cell growth and induce apoptosis by the production of oxidative stress in a variety of human cancer cells. However, the anti-cancer property and molecular mechanism of ZnO-NPs in human gingival squamous cell carcinoma (GSCC) are not fully understood. In this study, we found that ZnO-NPs induced growth inhibition of GSCC (Ca9-22 and OECM-1 cells), but no damage in human normal keratinocytes (HaCaT cells) and gingival fibroblasts (HGF-1 cells). ZnO-NPs caused apoptotic cell death of GSCC in a concentration-dependent manner by the quantitative assessment of oligonucleosomal DNA fragmentation. Flow cytometric analysis of cell cycle progression revealed that sub-G1 phase accumulation was dramatically induced by ZnO-NPs. In addition, ZnO-NPs increased the intracellular reactive oxygen species and specifically superoxide levels, and also decreased the mitochondrial membrane potential. ZnO-NPs further activated apoptotic cell death via the caspase cascades. Importantly, anti-oxidant and caspase inhibitor clearly prevented ZnO-NP-induced cell death, indicating the fact that superoxide-induced mitochondrial dysfunction is associated with the ZnO-NP-mediated caspase-dependent apoptosis in human GSCC. Moreover, ZnO-NPs significantly inhibited the phosphorylation of ribosomal protein S6 kinase (p70S6K kinase). In a corollary in vivo study, our results demonstrated that ZnO-NPs possessed an anti-cancer effect in a zebrafish xenograft model. Collectively, these results suggest that ZnO-NPs induce apoptosis through the mitochondrial oxidative damage and p70S6K signaling pathway in human GSCC. The present study may provide an experimental basis for ZnO-NPs to be considered as a promising novel anti-tumor agent for the treatment of gingival cancer. View Full-Text
Keywords: zinc oxide nanoparticles; gingival cancer; superoxide; p70S6K pathway zinc oxide nanoparticles; gingival cancer; superoxide; p70S6K pathway
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MDPI and ACS Style

Wang, S.-W.; Lee, C.-H.; Lin, M.-S.; Chi, C.-W.; Chen, Y.-J.; Wang, G.-S.; Liao, K.-W.; Chiu, L.-P.; Wu, S.-H.; Huang, D.-M.; Chen, L.; Shen, Y.-S. ZnO Nanoparticles Induced Caspase-Dependent Apoptosis in Gingival Squamous Cell Carcinoma through Mitochondrial Dysfunction and p70S6K Signaling Pathway. Int. J. Mol. Sci. 2020, 21, 1612. https://doi.org/10.3390/ijms21051612

AMA Style

Wang S-W, Lee C-H, Lin M-S, Chi C-W, Chen Y-J, Wang G-S, Liao K-W, Chiu L-P, Wu S-H, Huang D-M, Chen L, Shen Y-S. ZnO Nanoparticles Induced Caspase-Dependent Apoptosis in Gingival Squamous Cell Carcinoma through Mitochondrial Dysfunction and p70S6K Signaling Pathway. International Journal of Molecular Sciences. 2020; 21(5):1612. https://doi.org/10.3390/ijms21051612

Chicago/Turabian Style

Wang, Shih-Wei, Chien-Hsing Lee, Ming-Shen Lin, Chih-Wen Chi, Yu-Jen Chen, Guo-Shou Wang, Kuang-Wen Liao, Li-Pin Chiu, Shu-Hui Wu, Dong-Ming Huang, Luke Chen, and Yung-Shuen Shen. 2020. "ZnO Nanoparticles Induced Caspase-Dependent Apoptosis in Gingival Squamous Cell Carcinoma through Mitochondrial Dysfunction and p70S6K Signaling Pathway" International Journal of Molecular Sciences 21, no. 5: 1612. https://doi.org/10.3390/ijms21051612

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