Synergistic Effect of Nutlin-3 Combined with MG-132 on Schwannoma Cells Through Restoration of Merlin and p53 Tumour Suppressors

The growth patterns of sporadic vestibular schwannomas are highly variable, and only a small fraction of the tumours are fast-growing; however, the underlying mechanisms remain undefined. In this study, we observed differential NF2 gene alterations in correlation to clinical characteristics in sporadic schwannomas. The two genetic hits tended to occur in fast-growing tumours, which were characterized by the absence of the NF2 product merlin. The deregulation of p53-MDM2 axis 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. Inhibition of MDM2 by 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 demonstrate a difference in the sensitivity to Nutlin-3 between schwannoma cells with and without merlin expression. A combination of Nutlin-3 and MG-132 (a proteasome inhibitor), narrows this between-group difference and triggers stronger inhibitory effects on the growth of schwannomas through coordinated reactivation of p53. Taken together, we present treatment strategies directed on pathogenesis of sporadic schwannomas. Funding: This research was funded by the National Natural Science Foundation of China (Grant No. 81600815 to Yongchuan Chai, Grant No. 81371086 to Zhaoyan Wang, Grant No. 81570906 to Hao Wu). Declaration of Interest: The authors disclose no conflict of interest. Ethical Approval: All experimental protocols were approved by the Research Ethics Review Committee of Shanghai Jiao Tong University. Methods used in the present study were carried out in accordance with approved guidelines and regulations. It conformed to the provisions of the Declaration of Helsinki.