Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsResearch in context section
Background: The great majority of sporadic vestibular schwannomas (VSs) are due to the mutations of the NF2 gene encoding merlin. Sporadic VSs exhibit variable growth patterns and only a small fraction of the tumours are fast-growing; however, the underlying mechanisms remain undefined. Methods: DNA...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-10-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418304006 |
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doaj-92e2beea6a26475a8b1470192857ba05 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Hongsai Chen Lu Xue He Huang Hantao Wang Xiaoman Zhang Weidong Zhu Zhigang Wang Zhaoyan Wang Hao Wu |
| spellingShingle |
Hongsai Chen Lu Xue He Huang Hantao Wang Xiaoman Zhang Weidong Zhu Zhigang Wang Zhaoyan Wang Hao Wu Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsResearch in context section EBioMedicine |
| author_facet |
Hongsai Chen Lu Xue He Huang Hantao Wang Xiaoman Zhang Weidong Zhu Zhigang Wang Zhaoyan Wang Hao Wu |
| author_sort |
Hongsai Chen |
| title |
Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsResearch in context section |
| title_short |
Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsResearch in context section |
| title_full |
Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsResearch in context section |
| title_fullStr |
Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsResearch in context section |
| title_full_unstemmed |
Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsResearch in context section |
| title_sort |
synergistic effect of nutlin-3 combined with mg-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsresearch in context section |
| publisher |
Elsevier |
| series |
EBioMedicine |
| issn |
2352-3964 |
| publishDate |
2018-10-01 |
| description |
Background: The great majority of sporadic vestibular schwannomas (VSs) are due to the mutations of the NF2 gene encoding merlin. Sporadic VSs exhibit variable growth patterns and only a small fraction of the tumours are fast-growing; however, the underlying mechanisms remain undefined. Methods: DNA sequencing and dosage analysis were used to identify the NF2 mutation status in sporadic schwannomas. The expression and sub-cellular localization of merlin and p53-MDM2 were assessed by immunoblotting, qRT-PCR and immunofluorescence. In vitro and in vivo studies were performed to reveal the effects of Nutlin-3 (a MDM2 inhibitor) and/or MG-132(a proteasome inhibitor) on schwannomas. The proliferation of schwannoma cells was assessed by CCK-8 assay, EdU staining and Flow cytometry analysis. Findings: Double genetic hits of NF2 tended to occur in fast-growing tumours, characterized by the absence of merlin. The deregulation of p53-MDM2 was demonstrated to mediate merlin-deficient tumour growth, characterized by a nuclear accumulation of stabilized MDM2, contributing to a nuclear export of p53 for degradation. Nutlin-3 blocked the proliferation of schwannoma cells via a cooperative recovery of merlin and p53, accompanied by the shuttling of both proteins from the cytoplasm to the nucleus. We further demonstrated a difference in the sensitivity to Nutlin-3 between schwannoma cells with and without merlin expression. Nutlin-3 combined with MG-132 narrowed this between-group difference and triggered stronger inhibitory effects on the growth of schwannomas through coordinated reactivation of p53. Interpretation: These findings present treatment strategies directed on the pathogenesis of sporadic schwannomas. Fund: National Natural Science Foundation of China. Keywords: Schwannomas, NF2, p53, Mechanisms, Treatment |
| url |
http://www.sciencedirect.com/science/article/pii/S2352396418304006 |
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doaj-92e2beea6a26475a8b1470192857ba052020-11-25T01:29:08ZengElsevierEBioMedicine2352-39642018-10-0136252265Synergistic effect of Nutlin-3 combined with MG-132 on schwannoma cells through restoration of merlin and p53 tumour suppressorsResearch in context sectionHongsai Chen0Lu Xue1He Huang2Hantao Wang3Xiaoman Zhang4Weidong Zhu5Zhigang Wang6Zhaoyan Wang7Hao Wu8Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China; Shanghai Institute of Precision Medicine, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, ChinaDepartment of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, ChinaDepartment of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, ChinaDepartment of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, ChinaDepartment of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, ChinaDepartment of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, ChinaDepartment of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China; Corresponding authors at: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China.Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China; Corresponding authors at: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China.Background: The great majority of sporadic vestibular schwannomas (VSs) are due to the mutations of the NF2 gene encoding merlin. Sporadic VSs exhibit variable growth patterns and only a small fraction of the tumours are fast-growing; however, the underlying mechanisms remain undefined. Methods: DNA sequencing and dosage analysis were used to identify the NF2 mutation status in sporadic schwannomas. The expression and sub-cellular localization of merlin and p53-MDM2 were assessed by immunoblotting, qRT-PCR and immunofluorescence. In vitro and in vivo studies were performed to reveal the effects of Nutlin-3 (a MDM2 inhibitor) and/or MG-132(a proteasome inhibitor) on schwannomas. The proliferation of schwannoma cells was assessed by CCK-8 assay, EdU staining and Flow cytometry analysis. Findings: Double genetic hits of NF2 tended to occur in fast-growing tumours, characterized by the absence of merlin. The deregulation of p53-MDM2 was demonstrated to mediate merlin-deficient tumour growth, characterized by a nuclear accumulation of stabilized MDM2, contributing to a nuclear export of p53 for degradation. Nutlin-3 blocked the proliferation of schwannoma cells via a cooperative recovery of merlin and p53, accompanied by the shuttling of both proteins from the cytoplasm to the nucleus. We further demonstrated a difference in the sensitivity to Nutlin-3 between schwannoma cells with and without merlin expression. Nutlin-3 combined with MG-132 narrowed this between-group difference and triggered stronger inhibitory effects on the growth of schwannomas through coordinated reactivation of p53. Interpretation: These findings present treatment strategies directed on the pathogenesis of sporadic schwannomas. Fund: National Natural Science Foundation of China. Keywords: Schwannomas, NF2, p53, Mechanisms, Treatmenthttp://www.sciencedirect.com/science/article/pii/S2352396418304006 |