NF-\u03baB suppresses apoptosis and promotes bladder cancer cell proliferation by upregulating survivin expression in vitro and in vivo

Xiaolu Cui,Yu Zeng,Xiankui Liu,Chuize Kong,Xuyong Lin,Dezhi Shen,Zhe Zhang

doi:10.1038/srep40723

Abstract

Nuclear factor kappa-B (NF-κB) activation is a common phenomenon in cancers, which results in the aberrant expression of NF-κB target genes and leads to malignant transformation, metastatic dissemination, abnormal cell proliferation or resistance to cell death. Survivin is a unique member of the IAP family, a well-known cancer-specific molecule and a molecular marker of poor clinical outcome in several cancer types, including bladder cancer. YM-155, a potent survivin suppressor, has been shown to have anti-tumor activity in preclinical cell lines, xenograft models and phase I/II studies. In the present study, we investigated the function of the NF-κB/survivin pathway in bladder cancer. We found that NF-κB can promote cell cycle progression and reduce apoptosis by upregulating survivin expression, thereby increasing cellular proliferation. We further confirmed the tumorigenic function of the NF-κB/survivin pathway in vivo using a xenograft tumor model of stable NF-κB-overexpressing 5637 cells. Moreover, we found that YM-155 significantly induced apoptosis and decreased cellular proliferation as well as tumor growth in mice. Our results demonstrate the carcinogenic function of the NF-κB/survivin pathway in bladder cancer and the role of YM-155 as a promising agent for the strategic treatment of bladder cancer.

Highlights

Predictor of bladder cancer recurrence and cancer-specific survival[17,20,21]
Expression of NF-κB and survivin is upregulated in bladder cancer cell lines and tissue specimens, and a positive correlation is detected in tumor tissue specimens
Survivin and NF-κB p65 were highly expressed in high-grade tumors, tumors with metastases and Lymphatic invasion. These results suggest that the expression of survivin and NF-κBp65/RelA is remarkably upregulated in bladder cancer cell lines and tissues and closely correlated with the clinical progression of bladder cancer, expression of the two proteins is positively correlated in bladder cancer tissue specimens

Summary

Introduction

An in-depth study targeting the survivin regulation network is being pursued for novel anti-cancer therapeutics. The importance of the regulatory function of NF-κB in cancer is in the transcription of growth-promoting and anti-apoptotic genes. The precise mechanisms of NF-κBactivation and its regulatory role in cell survival and anti-apoptosis in bladder cancer remain unclear. We investigated the mechanisms of cell survival in bladder cancer cells. We confirmed that NF-κB activation contributes to the upregulation of the survivin gene in bladder cancer, and we revealed that by upregulating survivin expression, NF-κBenhances the proliferation and suppresses the apoptosis of bladder cancer cell lines both in vitro and in vivo. YM-155, a selective inhibitor of survivin, efficiently inhibited survivin expression and xenograft tumor growth

Methods

Results

Conclusion