Oligomannurarate sulfate blocks tumor growth by inhibiting NF-κB activation

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-kappa B activation status was determined using immunofluorescence, Western blotting, DNA-binding and transcription-activity assays. The effect of JG3 on upstream components of the NF-kappa B pathway and on selected transcription factors were monitored by Western blotting. The antitumor effect of JG3 and its relation to NF-kappa B activation were evaluated using four different tumor xenograft models. Results: We found that JG3 effectively inhibited NF-kappa B activation independent of heparanase expression. Our results indicate that JG3 inactivated NF-kappa B by interfering with the activation of upstream components of the NF-kappa B 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-kappa B was constitutively active (BEL-7402 liver carcinoma and MDA-MB-435s breast carcinoma), but did not affect the growth of tumors derived from NF-kappa B-negative cell lines (SGC-7901 gastric cancer and HO-8910 ovarian carcinoma). Conclusion: Our data indicate that NF-kappa B 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.