Phenethyl isothiocyanate induces DNA damage-associated G2/M arrest and subsequent apoptosis in oral cancer cells with varying p53 mutations |
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| Institution: | 1. Department of Medical Laboratory Sciences and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung City 83102, Taiwan;2. Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan;1. Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia;2. St. Petersburg State University, Russia;1. Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan;2. Radiation Oncology Division, National Cancer Center Hospital, Tokyo, Japan;3. Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan;4. Department of Radiology and Radiation Oncology, Kitasato University School of Medicine, Kanagawa, Japan;5. Department of Gastroenterology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan;6. Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan;7. Department of Therapeutic Radiation Oncology, Aichi Cancer Center Hospital, Aichi, Japan;8. Department of Radiation Oncology, Gunma Prefectural Cancer Center, Gunma, Japan;1. Department of Clinical Pathology and Hematology, Hospital Israelita Albert Einstein, São Paulo, Brazil;2. Department of Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, São Paulo, Brazil;1. Division of Molecular Signaling and Biochemistry, Department of Health Promotion, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan;2. Center for Oral Biological Research, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan;3. Division of Oral Pathology, Department of Health Promotion, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan;4. Division of Oral Anesthesiology, Department of Control of Physical Function, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan;1. Center of Molecular Medicine, CEITEC—Central European Institute of Technology, Masaryk University, Brno, Czech Republic;2. Department of Internal Medicine—Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;3. Core Facility—Proteomics, CEITEC—Central European Institute of Technology, Masaryk University, Brno, Czech Republic |
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| Abstract: | Phenethyl isothiocyanate (PEITC) is a naturally occurring cruciferous vegetable-derived compound that inhibits cell growth and induces apoptosis in oral cancer cells. However, the exact mechanism of PEITC action has not been fully elucidated. This study investigated the molecular mechanism and anticancer potential of PEITC in oral squamous cell carcinoma (OSCC) cells with various p53 statuses. PEITC inhibited the growth of OC2, SCC4, and SCC25 cells (functional p53 mutants) in a dose-dependent manner with low toxicity to normal cells. Treatment with PEITC induced reactive oxygen species production, nitric oxide generation, and GSH depletion and triggered DNA damage response as evidenced by flow cytometry, 8-OHdG formation, and comet assay. Furthermore, the subsequent activation of ATM, Chk2, and p53 as well as the increased expression of downstream proteins p21 and Bax resulted in a G2/M phase arrest by inhibiting Cdc25C, Cdc2, and cyclin B1. The PEITC-induced apoptotic cell death, following a diminished mitochondrial transmembrane potential, reduced the expression of Bcl-2 and Mcl-1, released mitochondrial cytochrome c, and activated caspase 3 and PARP cleavage. The p53 inhibitor pifithrin-α and the antioxidants N-acetylcysteine and glutathione (GSH) protected the cells from PEITC-mediated apoptosis. However, mito-TEMPO, catalase, apocynin, and L-NAME did not prevent PEITC-induced cell death, suggesting that PEITC induced G2/M phase arrest and apoptosis in oral cancer cells via a GSH redox stress and oxidative DNA damage-induced ATM–Chk2–p53-related pathway. These results provide new insights into the critical roles of both GSH redox stress and p53 in the regulation of PEITC-induced G2/M cell cycle arrest and apoptosis in OSCCs. |
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| Keywords: | Phenethyl isothiocyanates Oral squamous cell carcinoma p53 Reactive oxygen species Glutathione DNA damage Apoptosis Free radicals |
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