Abstract
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.
Highlights
Angiogenesis is a physiological process through which new blood vessels grow form existing vessels and is responsible for embryonic development, and tissue organ regeneration
Hypoxia greatly decreases the prolyl hydroxylation of HIF-1α resulting from inhibition of prolyl hydroxylase (PHD) activity, thereby increasing the stability and the nuclear level of HIF-1α, where it forms an active complex with HIF-1β and triggers the transcription of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF)
As angiogenesis is essential for tumor metastasis, the effects of Low molecular weight fucoidan (LMWF) on the migration and invasion of T24 cells were evaluated
Summary
Angiogenesis is a physiological process through which new blood vessels grow form existing vessels and is responsible for embryonic development, and tissue organ regeneration. It has been demonstrated that the growth and spread of cancer are highly dependent on angiogenesis for feeding growing tumors with nutrients and oxygen [1,2,3]. Hypoxia is a crucial stimulating factor for tumor angiogenesis and metastasis because it increases hypoxia-inducible factors-1 (HIF-1), a nuclear transcription factor, protein accumulation and transcriptional activity [6,7,8]. The proline residues of the oxygen-dependent degradation domain (ODDD) in HIF-1α are hydroxylated by prolyl hydroxylase (PHD). Hypoxia greatly decreases the prolyl hydroxylation of HIF-1α resulting from inhibition of PHD activity, thereby increasing the stability and the nuclear level of HIF-1α, where it forms an active complex with HIF-1β and triggers the transcription of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF). The overexpression of HIF-1α has been confirmed in human tumors as compared with that in the respective normal tissues [10], and blocking
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