Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Acta Pharmacol Sin. 2010 Mar;31(3):375-81. doi: 10.1038/aps.2010.13. Epub 2010 Feb 15.
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.
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.
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).
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.
新型海洋来源寡糖 JG3 通过抑制肝素酶活性显著抑制血管生成和肿瘤转移。它还能阻止肿瘤生长，但这种作用不能完全用其抗肝素酶活性来解释。本研究旨在确定 JG3 抑制肿瘤生长的作用机制。
通过 RT-PCR 和 Western blot 检测肝素酶表达。通过免疫荧光、Western blot、DNA 结合和转录活性测定评估 NF-κB 激活状态。通过 Western blot 监测 JG3 对 NF-κB 通路上游成分和选定转录因子的作用。采用四种不同的肿瘤异种移植模型评估 JG3 的抗肿瘤作用及其与 NF-κB 激活的关系。
我们发现 JG3 能有效抑制 NF-κB 激活，而与肝素酶表达无关。结果表明，JG3 通过干扰 NF-κB 通路上游成分的激活而不是普遍影响转录因子的核转位来使 NF-κB 失活。此外，体内研究表明 JG3 能有效阻止 NF-κB 持续激活的细胞系（BEL-7402 肝癌和 MDA-MB-435s 乳腺癌）来源的肿瘤生长，但不影响 NF-κB 阴性细胞系（SGC-7901 胃癌和 HO-8910 卵巢癌）来源的肿瘤生长。
我们的数据表明 NF-κB 介导了 JG3 诱导的肿瘤生长抑制。这些结果定义了 JG3 的一种新作用机制，并突出了 JG3 作为癌症治疗有前途的先导分子的潜力。
