Original Article

Oligomannurarate sulfate blocks tumor growth by inhibiting NF-κB activation

Authors: Jing Zhang, Yi Chen, Xian-liang Xin, Qiu-ning Li, Ming Li, Li-ping Lin, Mei-yu Geng, Jian Ding
DOI: 10.1038/aps.2010.13

Abstract

Aim: JG3, a novel marine-derived oligosaccharide, significantly inhibits angiogenesis and tumor metastasis by blocking heparanase activity. It also arrests tumor growth, an effect that is not fully explained by its anti-heparanase activity. Here we sought to identify the mechanisms underlying JG3-mediated inhibition of tumor growth.
Methods: Heparanase expression was assessed by RT-PCR and Western blotting. NF-κB activation status was determined using immunofluorescence, Western blotting, DNA-binding and transcription-activity assays. The effect of JG3 on upstream components of the NF-κB pathway and on selected transcription factors were monitored by Western blotting. The antitumor effect of JG3 and its relation to NF-κB activation were evaluated using four different tumor xenograft models.
Results: We found that JG3 effectively inhibited NF-κB activation independent of heparanase expression. Our results indicate that JG3 inactivated NF-κB by interfering with the activation of upstream components of the NF-κB pathway without generally affecting the nuclear translocation of transcription factors. Further,in vivo studies demonstrated that JG3 effectively arrested the growth of tumors derived from cell lines in which NF-κB was constitutively active (BEL-7402 liver carcinoma and MDA-MB-435s breast carcinoma), but did not affect the growth of tumors derived from NF-κB-negative cell lines (SGC-7901 gastric cancer and HO-8910 ovarian carcinoma).
Conclusion: Our data indicate that NF-κB mediates the JG3-induced arrest of tumor growth. These results define a new mechanism of action of JG3 and highlight the potential for JG3 as a promising lead molecule in cancer therapy.
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