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Multifunctional effects of honokiol as an anti-inflammatory and anti-cancer drug in human oral squamous cancer cells and xenograft |
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| Institution: | 1. Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 Plus, Chonbuk National University, Jeonju 651-756, Republic of Korea;2. Pohang Center for Evaluation of Biomaterials, Pohang, Gyeongbuk, Republic of Korea;3. Department of Oral Biochemistry, Dental Science Research Institute and the BK21 Project, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea;4. Department of Oral and Maxillofacial Surgery, Chonnam National University Hwasun Hospital, Gwangju, Republic of Korea;5. Department of Oral and Maxillofacial Surgery, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea;6. The Hormel Institute, University of Minnesota, Austin, MN, USA;7. Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan-gun, Jeonnam 534-729, Republic of Korea;1. Department of Neurosurgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, and West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China;2. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China;3. Institute of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China;1. Nanobiotechnology Center, University of Kentucky, Lexington, KY 40536, USA;2. Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA;3. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA;4. Department of Biostatistics, University of Kentucky, Lexington, KY 40536, USA;5. Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45267, USA;1. Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China;2. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China;1. Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China;2. Oncology Institute, Fourth Affiliated Hospital of Soochow University, Wuxi 214062, China;1. Department of Chemistry and Chemical Biology, Rutgers University, NJ, USA;2. Department of Chemical and Biochemical Engineering, Rutgers University, NJ, USA;3. Department of Biomedical Engineering, Rutgers University, NJ, USA;4. Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Rutgers University, Piscataway, NJ, USA;1. Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA;2. Laboratory of Molecular Immunoregulation, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA |
| Abstract: | The aim of this study was to investigate anti-inflammatory and anti-cancer effects of honokiol (HK) in two oral squamous cancer cell carcinoma (OSCC) cell lines, HN22 and HSC4, through the regulation of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum resident protein 44 (ERp44). Griess assay, zymography, and quantitative PCR were performed to study iNOS expression and subsequent nitric oxide (NO) production in OSCC cell lines. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis was used to elucidate the proteins associated with ER stress and cellular cytotoxic response induced by HK. Pull-down assay and molecular modeling were performed to better understand how HK interacts with ERp44. In vitro and in vivo experiments in which ERp44 expression was knocked down were performed to better understand the effects of ERp44 on a cellular level and anti-cancer effects of HK. Expression levels of iNOS and subsequent NO secretion were reduced in OSCC cell lines treated with HK. ERp44 was significantly decreased in OSCC cell lines by HK treatment. HK directly bound to ERp44, and ERp44 knock-down significantly inhibited oral cancer cell proliferation and colony formation. Moreover, HK treatment effectively inhibited tumor growth and ERp44 levels in BALB/c nude mice bearing HN22 cell xenografts. Our findings suggest that HK inhibited inflammation and induced apoptosis by suppressing both iNOS/NO and ERp44 expression in HN22 and HSC4 cells and xenograft tumors, and thus could be a potent anti-inflammatory and anti-cancer drug candidate for human oral cancer treatment. |
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