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Selective inhibition of nuclear factor-?B by nuclear factor-?B essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma.

ABSTRACT: Nuclear factor-?B (NF-?B) activation contributes to the development of metastasis, thus leading to a poor prognosis in many cancers, including OSCC. However, little in vivo experimental data are available about the effects of NF-?B inhibition on OSCC metastasis. OSCC sublines were established from a GFP-expressing parental cell line, GSAS, and designated GSAS/N3 and N5 according to the in vivo passage number after cervical lymph node metastasis by a serial orthotopic transplantation model. In vitro migration and invasion were assessed in these cells, and the NF-?B activities and expression of NF-?B-regulated metastasis-related molecules were also examined. In in vivo experiments, the metastasis and survival of tumor-engrafted mice were monitored. Furthermore, the effects of a selective NF-?B inhibitor, NEMO-binding domain (NBD) peptide, on metastasis in GSAS/N5-engrafted mice were assessed, and engrafted tongue tumors were immunohistochemically examined. Highly metastatic GSAS/N3 and N5 cells showed an enhanced NF-?B activity, thus contributing to increased migration, invasion, and a poor prognosis compared with the parent cells. Furthermore, the expression levels of NF-?B-regulated metastasis-related molecules, such as fibronectin, ?1 integrin, MMP-1, -2, -9, and -14, and VEGF-C, were upregulated in the highly metastatic cells. The NBD peptide suppressed metastasis and tongue tumor growth in GSAS/N5-inoculated mice, and was accompanied by the downregulation of the NF-?B-regulated metastasis-related molecules in engrafted tongue tumors. Our results suggest that the selective inhibition of NF-?B activation by NBD peptide may provide an effective approach for the treatment of highly metastatic OSCC.

SUBMITTER: Tanaka T

PROVIDER: S-EPMC7713617 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Selective inhibition of nuclear factor-κB by nuclear factor-κB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma.

Tanaka Takuya T Nakayama Hideki H Yoshitake Yoshihiro Y Irie Atsushi A Nagata Masashi M Kawahara Kenta K Takamune Yasuo Y Yoshida Ryoji R Nakagawa Yoshihiro Y Ogi Hidenao H Shinriki Satoru S Ota Kazutoshi K Hiraki Akimitsu A Ikebe Tetsuro T Nishimura Yasuharu Y Shinohara Masanori M

Cancer science 20120116 3

Nuclear factor-κB (NF-κB) activation contributes to the development of metastasis, thus leading to a poor prognosis in many cancers, including OSCC. However, little in vivo experimental data are available about the effects of NF-κB inhibition on OSCC metastasis. OSCC sublines were established from a GFP-expressing parental cell line, GSAS, and designated GSAS/N3 and N5 according to the in vivo passage number after cervical lymph node metastasis by a serial orthotopic transplantation model. In vi ...[more]

PMID: 22136381

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Project description:BackgroundCancer cell is generally characterized by enhanced glycolysis. Inflammasome activation is interaction with glycolysis. The concentration of lipopolysaccharide (LPS), a classic inflammasome activator, is significantly higher in colorectal cancer tissue than in normal intestinal mucosa. However, the mechanism of LPS on glycolysis and metastasis has not been fully elucidated. This study aimed to investigate the roles of LPS on inflammasome activation, glycolysis, and metastasis, and unravel metformin's potential in treatment of CRC.MethodsWe detected inflammasome activation and cell motility following LPS exposure in CRC cell lines. Glycolysis analysis was performed, and the key glycolytic rate-limiting enzymes were detected. Dual-luciferase reporter gene assay, co-immunoprecipitation, chromatin immunoprecipitation (ChIP) analysis, and ChIP-reChIP assay were performed to identify the specific mechanisms of LPS on glycolysis. Mouse metastasis models were used to determine the effects of LPS and metformin on metastasis. Correlation analysis of the expression of various molecules was performed in 635 CRC samples from The Cancer Genome Atlas and 83 CRC samples from our lab.ResultsLPS activates caspase-1 through NF-κB and upregulates the expression of Snail and HK3 depending on caspase-1 activation. LPS potentiates migration and invasion depending on accelerated glycolysis, which could be reversed by knockdown of glycolytic rate-limiting enzyme HK3. Nuclear Snail is upregulated by NF-κB under LPS treatment and then forms a complex with NF-κB, then directly binds to the HK3 promoter region to upregulate the expression of HK3. Metformin suppresses the NF-κB/Snail/HK3 signaling axis that is activated by LPS and then inhibits LPS-induced metastasis. In vivo, LPS-treated cells form more metastasis in the lungs of mice, and metformin completely reverses this effect of LPS.ConclusionLPS activates inflammasomes in cancer cells through NF-κB and promotes metastasis through glycolysis enhanced by the NF-κB/Snail/HK3 signaling pathway in CRC. Metformin could prevent this effect of LPS.

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Dataset Information

Selective inhibition of nuclear factor-?B by nuclear factor-?B essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma.

Publications

Selective inhibition of nuclear factor-κB by nuclear factor-κB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma.

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