Oligomannurarate sulfate blocks tumor growth by inhibiting NF-κB activation

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.

Introduction

Previous results from our group revealed that JG3 (Supplementary Figure 1A), a novel marine-derived oligosaccharide, significantly inhibits lung metastasis in a murine B16F10 experimental metastasis model, as well as angiogenesis and lung metastasis of MDA-MB-435s orthotopic xenografts in athymic mice. These effects were mediated by inhibition of heparanase activity via binding of JG3 to the KKDC and QPLK domains within heparanase

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Acknowledgements

The project was supported by Natural Science Foundation of China for Distinguished Young Scholars (No 30725046), National Basic Research Program Grant of China (No 2003CB716400), Natural Science Foundation of China for Innovation Research Group (No 30721005), the Knowledge Innovation Program of Chinese Academy of Sciences (No KSCX2-YWR-25), Key New Drug Creation and Manufacturing Program (No 2009ZX09103-073), 863 Hi-Tech Program of China (No 2006AA020602).

Author information

Authors and Affiliations

1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

   **g Zhang, Yi Chen, ** Lin, Mei-yu Geng & Jian Ding

Corresponding authors

Correspondence to Mei-yu Geng or Jian Ding.

Supplementary information

Supplementary information

(A) structure of JG3. (B) NF-κB activation status in four tumor cell lines. (DOC 556 kb)

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Zhang, J., Chen, Y., **n, Xl. et al. Oligomannurarate sulfate blocks tumor growth by inhibiting NF-κB activation. Acta Pharmacol Sin 31, 375–381 (2010). https://doi.org/10.1038/aps.2010.13

• Received: 24 December 2009

• Accepted: 15 January 2010

• Published: 15 February 2010

• Issue Date: March 2010

• DOI: https://doi.org/10.1038/aps.2010.13

• Springer Nature Singapore Pte Ltd.

Keywords

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