Endoplasmic reticulum stress is involved in hydrogen peroxide induced apoptosis in immortalized and malignant human oral keratinocytes |
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| Authors: | Seung-Ki Min Sun-Kyung Lee Jae-Sang Park Jun Lee Jun-Young Paeng Sang-Im Lee Hwa-Jeong Lee Youngho Kim Hyun-Ock Pae Suk-Keun Lee Eun-Cheol Kim |
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| Affiliation: | Department of Oral and Maxillofacial Surgery, College of Dentistry, Wonkwang University, Iksan, South Korea;;Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang University, Iksan, South Korea;;Department of Biochemistry, College of Medicine, Wonkwang University, Iksan, South Korea;;Department of Microbiology and Immunology, College of Medicine, Wonkwang University, Iksan, South Korea;;Department of Oral Pathology, College of Dentistry, Kangnung National University, Gangneung, South Korea |
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| Abstract: | Background: Although hydrogen peroxide may play an important role in the development of cancer, it can be an efficient inducer of apoptosis in cancer cells; the exact mechanism by which this action occurs is not completely understood in oral cancer cells. Method: In this study, the mechanisms by which H2O2 inhibited growth and induced apoptosis were differentially investigated using HPV‐immortalized human oral keratinocytes (IHOK) and oral cancer cells (HN4). Results: H2O2 treatment sensitively and dose‐dependently induced growth inhibition and typical apoptosis in IHOK and HN4 cells, as demonstrated by a decreased level of cell viability, an increased population of cells in the sub‐G0/G1 phase, ladder formation of the genomic DNA, chromatin condensation and accumulation of Annexin V+/PI+ cells. Furthermore, the expression of Bax, p53 and p21WAF1/CIP1 increased, whereas the expression of Bcl‐2 decreased in immortalized and malignant keratinocytes that were treated with H2O2. In addition, cytochrome‐c from the mitochondria was observed in H2O2‐treated IHOK and oral cancer cells, and this was accompanied by the activation of caspase‐3 and ‐9. Additionally, H2O2 treatment induced upregulation of CHOP, GRP78 and several representative endoplasmic reticulum (ER) stress‐responsive proteins, including heme oxygenase‐1. Conclusion: Overall, these results suggest that H2O2 triggers apoptosis via the mitochondrial and ER stress pathway in IHOK and HN4 cells, and that increasing the cellular levels of H2O2 sufficiently may lead to selective killing of oral cancer cells and therefore be therapeutically useful. |
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| Keywords: | apoptosis ER stress growth HO-1 hydrogen peroxide immortalized keratinocytes mitochondria oral cancer |
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