title: Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation of HIF-1/VEGF Signaling under Hypoxia.
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.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11483, Taiwan. sport315@gmail.com.
authors.forename: Meng-Chuan
authors.initials: MC
authors.lastname: Chen
authors.affiliation: School of Medicine, Tzu Chi University, Hualien 97002, Taiwan. hwl@tzuchi.com.tw.|Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Hualien 97002, Taiwan. hwl@tzuchi.com.tw.
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Seafood Technology Division, Fisheries Research Institute, Council of Agriculture, Keelung 20246, Taiwan. pahwang@mail.tfrin.gov.tw.
authors.forename: Pai-An
authors.initials: PA
authors.lastname: Hwang
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11483, Taiwan. tcchou48@mail.tcu.edu.tw.|Institute of Medical Sciences, Tzu Chi University, Hualien 97002, Taiwan. tcchou48@mail.tcu.edu.tw.|Department of Biotechnology, Asia University, Taichung 41354, Taiwan. tcchou48@mail.tcu.edu.tw.|China Medical University Hospital, China Medical University, Taichung 40447, Taiwan. tcchou48@mail.tcu.edu.tw.
authors.forename: Tz-Chong
authors.initials: TC
authors.lastname: Chou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011134:Polysaccharides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011134:Polysaccharides; D042461:Vascular Endothelial Growth Factor A; C007789:fucoidan
keywords: angiogenesis; bladder cancer; hypoxia-inducible factor 1 alpha; low molecular weight fucoidan; vascular endothelial growth factor