Oligomannurarate sulfate blocks tumor growth by inhibiting NF-kappaB activation.
OBJECTIVE
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-kappaB activation status was determined using immunofluorescence, Western blotting, DNA-binding and transcription-activity assays. The effect of JG3 on upstream components of the NF-kappaB pathway and on selected transcription factors were monitored by Western blotting. The antitumor effect of JG3 and its relation to NF-kappaB activation were evaluated using four different tumor xenograft models.


RESULTS
We found that JG3 effectively inhibited NF-kappaB activation independent of heparanase expression. Our results indicate that JG3 inactivated NF-kappaB by interfering with the activation of upstream components of the NF-kappaB 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-kappaB was constitutively active (BEL-7402 liver carcinoma and MDA-MB-435s breast carcinoma), but did not affect the growth of tumors derived from NF-kappaB-negative cell lines (SGC-7901 gastric cancer and HO-8910 ovarian carcinoma).


CONCLUSIONS
Our data indicate that NF-kappaB 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.
Zhang
Jing
J
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Chen
Yi
Y
Xin
Xian-liang
XL
Li
Qiu-ning
QN
Li
Ming
M
Lin
Li-ping
LP
Geng
Mei-yu
MY
Ding
Jian
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D019763:Heparin Lyase / Q000378:metabolism; D006801:Humans; D008351:Mannans / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D008351:Mannans; D016328:NF-kappa B; C524388:oligomannurarate sulfate; D019763:Heparin Lyase