The first 3 authors contributed equally to this work.
Activation of nuclear factor κB pathway and downstream targets survivin and livin by SHARPIN contributes to the progression and metastasis of prostate cancer
Article first published online: 12 JUN 2014
© 2014 American Cancer Society
Volume 120, Issue 20, pages 3208–3218, October 15, 2014
How to Cite
Zhang, Y., Huang, H., Zhou, H., Du, T., Zeng, L., Cao, Y., Chen, J., Lai, Y., Li, J., Wang, G. and Guo, Z. (2014), Activation of nuclear factor κB pathway and downstream targets survivin and livin by SHARPIN contributes to the progression and metastasis of prostate cancer. Cancer, 120: 3208–3218. doi: 10.1002/cncr.28796
We thank Dr. Wang He and Dr. Pei Wang for reviewing this article.
- Issue published online: 3 OCT 2014
- Article first published online: 12 JUN 2014
- Manuscript Accepted: 21 APR 2014
- Manuscript Revised: 10 APR 2014
- Manuscript Received: 20 FEB 2014
- NFκB pathway;
- prostate cancer;
Nuclear factor κB (NFκB) signaling is strongly associated with tumor progression, and studies have shown that SHANK-associated RH domain interacting protein (SHARPIN) is crucial for NFκB pathway activation. However, the expression and functions of SHARPIN in prostate cancer (PCa) have not yet been defined.
The expression of SHARPIN in PCa cell lines and tissues was evaluated with western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. After SHARPIN was silenced in the PCa cell lines, western blots were used to confirm that SHARPIN physically associated with components of the NFκB pathway and the downstream targets (survivin and livin). The functions of SHARPIN in cell proliferation, migration, and invasion in vitro were measured with 5-(3-carboxymethoxyphenyl)-2-(4,5-dimenthylthiazoly)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS), Transwell, and invasion assays, respectively. Flow cytometry was employed to evaluate cell apoptosis. Furthermore, tumorigenesis in vivo was examined with tumorigenicity assays.
SHARPIN expression was upregulated in PCa cell lines and tissues. The knockdown of SHARPIN or incubation with Bay 11-7082 (an NFκB inhibitor) led to dramatically decreased levels of phosphorylated IκBα and phosphorylated p65 in comparison with the control group. Downregulation of survivin and livin due to SHARPIN inhibition was attributable to transcriptional repression (P < .05). Decreases in cell viability, migration, invasion, and survival with a higher sensitivity to docetaxel in vitro and with repressed tumorigenesis in vivo were observed upon SHARPIN silencing, and this was consistent with the results from inhibition of the NFκB pathway and its downstream targets.
The current study demonstrates that overexpression of SHARPIN promotes activation of the NFκB pathway and downstream targets survivin and livin, which potentially contributes to PCa development. Cancer 2014;120:3208–3218. ©2014 American Cancer Society.