The Pharmacological NF-κB Inhibitor BAY11-7082 Induces Cell Apoptosis and Inhibits the Migration of Human Uveal Melanoma Cells

Shuiqing Hu,Shengfang Ge,Fuxiang Chen,Xianqun Fan,Qingqiong Luo,Biyun Cun,Dan Hu

doi:10.3390/ijms131215653

Abstract

Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy. The identification of important survival pathways in uveal melanomas provides novel therapeutic targets for effective treatment. In the present study, we found that the NF-κB signaling pathway was constitutively and highly activated in uveal melanoma cells. Treatment with the pharmacological NF-κB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-κB. In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle. The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment. Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax. Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo. Collectively, the present study identified NF-κB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-κB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma.

Highlights

Uveal melanomas, including ciliary body, iris and choroidal melanomas, are the most common primary intraocular tumors in adults [1,2,3,4]
NF-κB is a ubiquitously expressed transcription factor that is regulated by the cytoplasmic inhibitor protein IκBα, which inhibits NF-κB translocation by masking the nuclear localization signals of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm [5]
With the treatment of NF-κB specific inhibitor BAY11-7082 for 2 h, translocation of p65 in the nucleus decreased significantly as shown by the reduced staining in the nucleus, and relocated in the cytoplasm (Figure 1B). These findings indicated that NF-κB is constitutively activated in the four untreated uveal melanoma cells and the specific inhibitor

Summary

Introduction

Uveal melanomas, including ciliary body, iris and choroidal melanomas, are the most common primary intraocular tumors in adults [1,2,3,4]. Many options are currently available for the treatment of uveal melanomas, such as enucleation, plaque radiotherapy, proton beam radiotherapy and transpupillary thermotherapy. The five-year survival rate for uveal melanoma is 75%, which is comparable to cutaneous melanoma. Metastases to the liver in uveal melanoma patients remain the leading cause of death. The average survival time for patients diagnosed with liver metastasis is only from 2 to 14 months, and up to 95% of patients with uveal melanoma have already developed liver metastases at the time of death. It is an urgent necessity to develop more efficient and novel therapeutic agents for improving the survival of uveal melanoma patients [2,3]

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Results

Conclusion