title: Fucoidan inhibition of lung cancer in vivo and in vitro : role of the Smurf2-dependent ubiquitin proteasome pathway in TGFβ receptor degradation.
abstract: Fucoidan, a polysaccharide extracted from brown seaweeds, reduces tumor cell proliferation. In this study, we demonstrate that fucoidan reduces tumor size in LLC1-xenograft male C57BL/6 mice. Moreover, we found that LLC1-bearing mice continuously fed fucoidan showed greater antitumor activity than mice with discontinuous feeding. Fucoidan inhibited the in vitro growth of lung cancer cells. Transforming growth factor β (TGFβ) receptors (TGFRs) play important roles in the regulation of proliferation and progression, and high TGFRI expression in lung cancer specimens is associated with a worse prognosis. Herein, using lung cancer cells, we found that fucoidan effectively reduces TGFRI and TGFRII protein levels in vivo and in vitro. Moreover, fucoidan reduces TGFR downstream signaling events, including those in Smad2/3 and non-Smad pathways: Akt, Erk1/2, and FAK phosphorylation. Furthermore, fucoidan suppresses lung cancer cell mobility upon TGFβ stimulation. To elucidate how fucoidan decreases TGFR proteins in lung cancer cells, we found that fucoidan enhances the ubiquitination proteasome pathway (UPP)-mediated degradation of TGFRs in A549 and CL1-5 cells. Mechanistically, fucoidan promotes Smurf2 and Smad7 to conjugate TGFRs, resulting in TGF degradation; however, Smurf2-shRNA abolishes fucoidan-enhanced UPP-mediated TGFR degradation. Our study is the first to identify a novel mechanism for the antitumor activity of fucoidan, namely decreasing tumor growth by modulating the TGFR/Smad7/Smurf2-dependent axis, leading to TGFR protein degradation and inhibition of lung cancer cell progression in vitro and in vivo. Our current findings indicate that fucoidan is a potential therapeutic agent or dietary supplementation for lung cancer, acting via the Smurf2-dependent ubiquitin degradation of TGFβ receptors.
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan. The Genomics Research Center, Academia Sinica, Taipei, Taiwan. Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan. Contributed equally to this work.
authors.forename: Hsien-Yeh
authors.initials: HY
authors.lastname: Hsu
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan. Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan. Contributed equally to this work.
authors.forename: Tung-Yi
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Chung
authors.initials: YC
authors.lastname: Wu
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Tsao
authors.affiliation: Seafood Technology Division, Fisheries Research Institute, Council of Agriculture, Keelung, Taiwan.
authors.forename: Pai-An
authors.initials: PA
authors.lastname: Hwang
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Shih
authors.affiliation: Fordham University, New York, NY, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Hsu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011134:Polysaccharides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011134:Polysaccharides; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D025801:Ubiquitin; C007789:fucoidan; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex