Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation
Abstract Background Oral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. We investigated the r...
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| Format: | Article |
| Language: | English |
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BMC
2018-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0760-0 |
| _version_ | 1818028969392340992 |
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| author | Yuan-Hua Wu Wun-Syuan Wu Li-Ching Lin Chiang-Shin Liu Sheng-Yow Ho Bour-Jr Wang Bu-Miin Huang Ya-Ling Yeh Hui-Wen Chiu Wei-Lei Yang Ying-Jan Wang |
| author_facet | Yuan-Hua Wu Wun-Syuan Wu Li-Ching Lin Chiang-Shin Liu Sheng-Yow Ho Bour-Jr Wang Bu-Miin Huang Ya-Ling Yeh Hui-Wen Chiu Wei-Lei Yang Ying-Jan Wang |
| author_sort | Yuan-Hua Wu |
| collection | DOAJ |
| description | Abstract Background Oral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. We investigated the role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in OSCC cells treated with bortezomib (a proteasome inhibitor) combined with irradiation (IR) treatment. Methods The effects of combined treatment in OSCC cells were investigated using assays of cell viability, autophagy, apoptosis, western blotting, and immunofluorescence staining. The ubiquitination of proteins was analyzed by immunoprecipitation. Stable knockdown of TRAF6 in OSCC cells was constructed with lentivirus. The xenograft murine models were used to observe tumor growth. Results We found synergistic effects of bortezomib and IR on the viability of human oral cancer cells. The combination of bortezomib and IR treatment induced autophagic cell death. Furthermore, bortezomib inhibited IR-induced TRAF6 ubiquitination and inhibited TRAF6-mediated Akt activation. Bortezomib reduced TRAF6 protein expression through autophagy-mediated lysosomal degradation. TRAF6 played an oncogenic role in tumorigenesis of human oral cancer cells and oral tumor growth was suppressed by bortezomib and IR treatment. In addition, OSCC patients with expression of TRAF6 showed a trend towards poorer cancer-specific survival when compared with patients without TRAF6 expression. Conclusions A combination of a proteasome inhibitor, IR treatment and TRAF6 inhibition could be a novel therapeutic strategy in OSCC. |
| first_indexed | 2024-12-10T05:12:14Z |
| format | Article |
| id | doaj.art-2bc76979fc334b06add774627e38b2cd |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T05:12:14Z |
| publishDate | 2018-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-2bc76979fc334b06add774627e38b2cd2022-12-22T02:01:03ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-04-0137111410.1186/s13046-018-0760-0Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradationYuan-Hua Wu0Wun-Syuan Wu1Li-Ching Lin2Chiang-Shin Liu3Sheng-Yow Ho4Bour-Jr Wang5Bu-Miin Huang6Ya-Ling Yeh7Hui-Wen Chiu8Wei-Lei Yang9Ying-Jan Wang10Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung UniversityDepartment of Environmental and Occupational Health, College of Medicine, National Cheng Kung UniversityDepartment of Radiation Oncology, Chi Mei Medical CenterDepartment of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDepartment of Radiation Oncology, Chi Mei Medical Center, LiouyingDepartment of Occupational and Environmental Medicine, National Cheng Kung University HospitalDepartment of Cell Biology and Anatomy, College of Medicine, National Cheng Kung UniversityDepartment of Environmental and Occupational Health, College of Medicine, National Cheng Kung UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityThe University of Texas MD Anderson Cancer CenterDepartment of Environmental and Occupational Health, College of Medicine, National Cheng Kung UniversityAbstract Background Oral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. We investigated the role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in OSCC cells treated with bortezomib (a proteasome inhibitor) combined with irradiation (IR) treatment. Methods The effects of combined treatment in OSCC cells were investigated using assays of cell viability, autophagy, apoptosis, western blotting, and immunofluorescence staining. The ubiquitination of proteins was analyzed by immunoprecipitation. Stable knockdown of TRAF6 in OSCC cells was constructed with lentivirus. The xenograft murine models were used to observe tumor growth. Results We found synergistic effects of bortezomib and IR on the viability of human oral cancer cells. The combination of bortezomib and IR treatment induced autophagic cell death. Furthermore, bortezomib inhibited IR-induced TRAF6 ubiquitination and inhibited TRAF6-mediated Akt activation. Bortezomib reduced TRAF6 protein expression through autophagy-mediated lysosomal degradation. TRAF6 played an oncogenic role in tumorigenesis of human oral cancer cells and oral tumor growth was suppressed by bortezomib and IR treatment. In addition, OSCC patients with expression of TRAF6 showed a trend towards poorer cancer-specific survival when compared with patients without TRAF6 expression. Conclusions A combination of a proteasome inhibitor, IR treatment and TRAF6 inhibition could be a novel therapeutic strategy in OSCC.http://link.springer.com/article/10.1186/s13046-018-0760-0Oral squamous cell carcinomaRadiationTRAF6UbiquitinationAutophagy |
| spellingShingle | Yuan-Hua Wu Wun-Syuan Wu Li-Ching Lin Chiang-Shin Liu Sheng-Yow Ho Bour-Jr Wang Bu-Miin Huang Ya-Ling Yeh Hui-Wen Chiu Wei-Lei Yang Ying-Jan Wang Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation Journal of Experimental & Clinical Cancer Research Oral squamous cell carcinoma Radiation TRAF6 Ubiquitination Autophagy |
| title | Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation |
| title_full | Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation |
| title_fullStr | Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation |
| title_full_unstemmed | Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation |
| title_short | Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation |
| title_sort | bortezomib enhances radiosensitivity in oral cancer through inducing autophagy mediated traf6 oncoprotein degradation |
| topic | Oral squamous cell carcinoma Radiation TRAF6 Ubiquitination Autophagy |
| url | http://link.springer.com/article/10.1186/s13046-018-0760-0 |
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