Role of transcription factor Sp1 in the 4-O-methylhonokiol-mediated apoptotic effect on oral squamous cancer cells and xenograft |
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| Affiliation: | 1. Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Zagazig University, Egypt;2. Department of Medical Laboratories, Applied Medical Science College, Qassim University, Saudi Arabia;3. Department of Pathology, Faculty of Medicine, Zagazig University, Egypt;4. Department of Pathology, College of Medicine, Qassim University, Saudi Arabia;1. Department of Zoology, Institute of Ecology and Earth Sciences, University of Tartu, Vanemuise 46, Tartu 51003, Estonia;2. Instituto de Medicina Preventiva Veterinaria y Programa de Investigación Aplicada en Fauna Silvestre, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile;3. Laboratorio de Zoonosis Parasitarias, FCEyN, UNMdP, Funes 3350, CP: 7600 Mar del Plata, Buenos Aires, Argentina;4. Department of Parasitology, Faculty of Veterinary Medicine, University of Atatürk, Erzurum, Turkey;5. World Health Organization Collaborating Centre for the Epidemiology, Detection and Control of Cystic and Alveolar Echinococcosis, European Union Reference Laboratory for Parasites (EURLP), Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;6. Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia;7. Parasitology Department, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Majadahonda, Madrid 28220, Spain;8. Departamento de Genética, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, Porto Alegre, RS, Brazil;9. Parasitology and Mycology department, Mustapha University Hospital, 16000 Algiers, Algeria;10. Section of Parasitology, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India;11. School of Animal and Veterinary Sciences, Charles Sturt University, Locked Bag 588, Wagga Wagga, NSW 2678, Australia;12. Department of Veterinary Medicine, Università degli Studi di Milano, via Celoria 10, 20133 Milan, Italy;13. Department of Medical Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran;14. Laboratory of Medical and Molecular Parasitology-Mycology (LP3M), LR 12ES08, Faculty of Pharmacy, University of Monastir, 5000 Monastir, Tunisia;15. Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran;p. Department of Microbiology and Parasitology, Faculty of Medical Sciences, Comahue National University, Buenos Aires, 1400, 8300 Neuquén, Argentina;q. Department of Parasitology, Faculty of Pharmacy, Complutense University, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain;r. Merial GmbH, Kathrinenhof Research Center, Walchenseestr. 8–12, 83101 Rohrdorf, Germany;s. Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran;t. Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran;u. Department of Parasitology, Faculty of Veterinary Medicine, University of Firat, 23119 Elazig, Turkey;v. Centre for Infectious Disease Control Netherlands, National Institute for Public Health and Environment, P.O. Box 1, 3720, BA, Bilthoven, the Netherlands;w. Institute of Parasitology, Slovak Academy of Sciences, Košice, Hlinkova 3, 040 01 Košice, Slovakia;x. ANSES, Nancy Laboratory for Rabies and Wildlife, Wildlife surveillance and eco-epidemiology unit, Malzéville 54220, France;y. Laboratory of Parasitology, Veterinary Teaching Hospital, Department of Veterinary Medicine, University of Sassari, Via Vienna 2, 07100 Sassari, Italy |
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| Abstract: | Recently, biphenolic components derived from the Magnolia family have been studied for anti-cancer, anti-stress, and anti-inflammatory pharmacological effects. However, the pharmacological mechanism of action of 4-O-methylhonokiol (MH) is not clear in oral cancer. The aim of this study was to investigate the role of MH in apoptosis and its molecular mechanism in oral squamous cell carcinoma (OSCC) cell lines, HN22 and HSC4, as well as tumor xenografts. Here, we demonstrated that MH decreased cell growth and induced apoptosis in HN22 and HSC4 cells through the regulation of specificity protein 1 (Sp1). We employed several experimental techniques such as MTS assay, DAPI staining, PI staining, Annexin-V/7-ADD staining, RT-PCR, western blot analysis, immunocytochemistry, immunohistochemistry, TUNEL assay and in vivo xenograft model analysis. MH inhibited Sp1 protein expression and reduced Sp1 protein levels via both proteasome-dependent protein degradation and inhibition of protein synthesis in HN22 and HSC4 cells; MH did not alter Sp1 mRNA levels. We found that MH directly binds Sp1 by Sepharose 4B pull-down assay and molecular modeling. In addition, treatment with MH or knocking down Sp1 expression suppressed oral cancer cell colony formation. Moreover, MH treatment effectively inhibited tumor growth and Sp1 levels in BALB/c nude mice bearing HN22 cell xenografts. These results indicated that MH inhibited cell growth, colony formation and also induced apoptosis via Sp1 suppression in OSCC cells and xenograft tumors. Thus, MH is a potent anti-cancer drug candidate for oral cancer. |
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| Keywords: | Specificity protein 1 Oral squamous cell carcinoma Apoptosis Xenograft |
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