Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation of HIF-1/VEGF Signaling under Hypoxia.
Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation of HIF-1/VEGF Signaling under Hypoxia.
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DOI：
10.3390/md13074436
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发表时间：
2015-07-17
期刊：
影响因子：
5.4
通讯作者：
Chou TC
中科院分区：
文献类型：
--
作者：
Chen MC;Hsu WL;Hwang PA;Chou TC
缺氧诱导因子-1（hypoxia-inducible factors-1，HIF-1）的激活在促进肿瘤血管生成、生长和转移中起重要作用。低分子量岩藻依聚糖（LMWF）是从褐藻中提取的，具有抗癌活性。然而，LMWF是否减弱膀胱癌细胞中缺氧诱导的血管生成以及所涉及的分子机制尚不清楚。本研究首次证实LMWF可抑制缺氧刺激的H2 O2生成、HIF-1的积累和血管内皮生长因子（VEGF）的分泌，以及抑制缺氧人膀胱癌细胞（T24）的迁移和侵袭。LMWF还下调T24细胞中缺氧激活的PI 3 K/AKT/mTOR/p70 S6 K/4 EBP-1信号的磷酸化。阻断PI 3 K/AKT或mTOR活性可显著降低T24细胞中缺氧诱导的HIF-1α表达和VEGF分泌，支持PI 3 K/AKT/mTOR参与了HIF-1α和VEGF的诱导。此外，LMWF在体外和体内显著减弱血管生成，这通过减少缺氧人脐血管内皮细胞的管形成和肿瘤中的毛细血管生成来证明。同样，LMWF的给药也抑制了体内HIF-1α和VEGF的表达，并伴随着肿瘤生长的减少。综上所述，在缺氧条件下，LMWF在膀胱癌中的抗血管生成活性可能与抑制HIF-1/VEGF调节的信号通路有关。
Activation of hypoxia-induced hypoxia-inducible factors-1 (HIF-1) plays a critical role in promoting tumor angiogenesis, growth and metastasis. Low molecular weight fucoidan (LMWF) is prepared from brown algae, and exhibits anticancer activity. However, whether LMWF attenuates hypoxia-induced angiogenesis in bladder cancer cells and the molecular mechanisms involved remain unclear. This is the first study to demonstrate that LMWF can inhibit hypoxia-stimulated H2O2 formation, HIF-1 accumulation and transcriptional activity vascular endothelial growth factor (VEGF) secretion, and the migration and invasion in hypoxic human bladder cancer cells (T24) cells. LMWF also downregulated hypoxia-activated phosphorylation of PI3K/AKT/mTOR/p70S6K/4EBP-1 signaling in T24 cells. Blocking PI3K/AKT or mTOR activity strongly diminished hypoxia-induced HIF-1α expression and VEGF secretion in T24 cells, supporting the involvement of PI3K/AKT/mTOR in the induction of HIF-1α and VEGF. Additionally, LMWF significantly attenuated angiogenesis in vitro and in vivo evidenced by reduction of tube formation of hypoxic human umbilical vascular endothelial cells and blood capillary generation in the tumor. Similarly, administration of LMWF also inhibited the HIF-1α and VEGF expression in vivo, accompanied by a reduction of tumor growth. In summary, under hypoxia conditions, the antiangiogenic activity of LMWF in bladder cancer may be associated with suppressing HIF-1/VEGF-regulated signaling pathway.