Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation
of HIF-1/VEGF Signaling under Hypoxia
#MMPMID26193287
Chen MC
; Hsu WL
; Hwang PA
; Chou TC
Mar Drugs
2015[Jul]; 13
(7
): 4436-51
PMID26193287
show ga
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-1? expression and VEGF secretion in T24 cells, supporting the
involvement of PI3K/AKT/mTOR in the induction of HIF-1? 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-1? 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.
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