Activation of nuclear factor κB pathway and downstream targets survivin and livin by SHARPIN contributes to the progression and metastasis of prostate cancer

Abstract

BACKGROUND: Nuclear factor jB (NFjB) signaling is strongly associated with tumor progression, and studies have shown that SHANK-associated RH domain interacting protein (SHARPIN) is crucial for NFjB pathway activation. However, the expression and functions of SHARPIN in prostate cancer (PCa) have not yet been defined. METHODS: 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 NFjB 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. RESULTS: SHARPIN expression was upregulated in PCa cell lines and tissues. The knockdown of SHARPIN or incubation with Bay 11-7082 (an NFjB inhibitor) led to dramatically decreased levels of phosphorylated IjBa 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 NFjB pathway and its downstream targets. CONCLUSION: The current study demonstrates that overexpression of SHARPIN promotes activation of the NFjB pathway and downstream targets survivin and livin, which potentially contributes to PCa development. Cancer 2014;120:3208-18.

Livin enhances chemoresistance in head and neck squamous cell carcinoma

“…Therefore, in the present study, we investigated the role of Livin in determining susceptibility to commonly used chemotherapeutic drugs, such as docetaxel, cisplatin and 5-FU, in human HNSCC cell lines. Although several studies have described that Livin contribute to the resistance of various chemotherapeutic drugs including cisplatin in various cancers (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), the present study is the first to demonstrate the correlation between Livin and chemoresistance in human HNSCC.…”

“…Livin, a recently discovered IAP, is composed of a single BIR domain and a RING motif (9). Livin has been implicated in chemoresistance in various cancers (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). It has been reported to play a role in resistance to cisplatin in bladder cancer, renal carcinoma, gastic cancer, hepatocellular carcinoma, lung adenocarcinoma/ non-small cell carcinoma, osteosarcoma, colon cancer and ovarian carcinoma (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)31).…”

“…Zhu et al (22) demonstrated that miRNA-20a induces cisplatin resistance via targeting cylindromatosis (CYLD), leading to activation of nuclear factor (NF)-κB and downstream target Livin in gastric cancer. Activation of NF-κB pathway and downstream target Livin by SHANK-associated RH domain interacting protein (SHARPIN) contributed to docetaxel resistance in prostate cancer (34). In addition, Livin silencing increased cisplatin chemosensitivity involving Bcl-2 and Akt pathway in renal cell carcinoma (21).…”

Neuron-type-specific signaling by the p75NTR death receptor regulated by differential proteolytic cleavage

“…We found that NGF treatment for 24 h greatly induced the expression of NIAP (neuronal inhibitor of apoptosis protein, also known as NAIP) and Livin (also known as BIRC7), two anti-apoptotic genes regulated by the NF-kB pathway ( Fig. 3D; Busuttil et al, 2002;Zhang et al, 2014). NGF did not induce the expression of Bcl-2, Bcl-xL (encoded by BCL2L1), cIAP1 (also known as BIRC2), cIAP2 (also known as BIRC3), XIAP, Bruce (also known as BIRC6) or survivin (also known as BIRC5) in cultured CGNs (data not shown).…”

Emerging role of SHARPIN in hepatocellular carcinoma progression

“…SHARPIN expression was shown to be correlated with Akt activation, consistent with the abovementioned role of SHARPIN in inhibition of PTEN activity [15] . In prostate cancer, upregulated SHARPIN expression induces activation of the NF-κB pathway and its downstream targets Survivin and Livin [24] , which potentially inhibits apoptosis and contributes to tumor development.…”