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Low Molecular Weight Mannogalactofucans Derived from Undaria pinnatifida Induce Apoptotic Death of Human Prostate Cancer Cells In Vitro and In Vivo

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Abstract

Low molecular weight mannogalactofucans (LMMGFs) prepared by enzymatic degradation of high molecular weight Undaria galactofucan (MF) were evaluated for their anti-cancer effects against human prostate cancer. Correlation NMR and linkage analyses confirmed that LMMGFs consist mainly of α-fucose and β-galactose units: α-fucose units are 1,3-linked; β-galactose units are terminal, 1,3- and/or 1,6-linked; both sugars are partially sulphated, fucose at positions O-2 and/or O-4 and galactose at O-3. Mannose residue, as a minor sugar, presents as the 1,4-linked terminal units. LMMGFs more significantly induced cell cycle arrest at the G0/G1 phase and cell death via suppression of the Akt/GSK-3β/β-catenin pathway than MF in human PC-3 prostate cancer cells. LMMGFs upregulated mRNA expression of death receptor-5 (DR-5), the ratio of Bax to Bcl-2, the cleavage of caspases and PARP, the depolarisation of mitochondrial membrane potential, and ROS generation. LMMGFs (200–400 mg/kg) effectively reduced both tumour volume and size in a xenografted mouse model. These results demonstrated that LMMGFs attenuate the growth of human prostate cancer cells both in vitro and in vivo, suggesting that LMMGFs can be used as a potent functional ingredient in health-beneficial foods or as a therapeutic agent to prevent or treat androgen-independent human prostate cancer.

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References

  • Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9:400–414

    Article  CAS  Google Scholar 

  • Aisa Y, Miyakawa Y, Nakazato T, Shibata H, Saito K, Ikeda Y, Kizaki M (2005) Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and down-regulation of ERK pathways. Am J Hematol 78:7–14

    Article  CAS  Google Scholar 

  • Bilan MI, Grachev AA, Ustuzhanina NE, Shashkov AS, Nifantiev NE, Usov AI (2002) Structure of a fucoidan from the brown seaweed Fucus evanescens C.Ag. Carbohydr Res 337:719–730

    Article  CAS  Google Scholar 

  • Bilan MI, Grachev AA, Ustuzhanina NE, Shashkov AS, Nifantiev NE, Usov AI (2004) A highly regular fraction of a fucoidan from the brown seaweed Fucus distichus L. Carbohydr Res 339:511–517

    Article  CAS  Google Scholar 

  • Boo HJ, Hong JY, Kim SC, Kang JI, Kim MK, Kim EJ, Hyun JW, Koh YS, Yoo ES, Kwon JM, Kang HK (2013) The anticancer effect of fucoidan in PC-3 prostate cancer cells. Mar Drugs 11:2982–2999

    Article  Google Scholar 

  • Chabut D, Fischer AM, Colliec-Jouault S, Laurendeau I, Matou S, Le Bonniec B, Helley D (2003) Low molecular weight fucoidan and heparin enhance the basic fibroblast growth factor-induced tube formation of endothelial cells through heparan sulfate-dependent alpha 6 overexpression. Mol Pharmacol 64:696–702

    Article  CAS  Google Scholar 

  • Changotade SI, Korb G, Bassil J, Barroukh B, Willig C, Colliec-Jouault S, Durand P, Godeau G, Senni K (2008) Potential effects of a low-molecular-weight fucoidan extracted from brown algae on bone biomaterial osteoconductive properties. J Biomed Mater Res A 87:666–675

    Article  Google Scholar 

  • Choo GS, Lee HN, Shin SA, Kim HJ, Jung JY (2016) Anticancer effect of fucoidan on DU-145 prostate cancer cells through inhibition of PI3K/Akt and MAPK pathway expression. Mar Drugs 14:126

    Article  Google Scholar 

  • Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656

    Article  CAS  Google Scholar 

  • Denicourt C, Dowdy SF (2004) Cip/Kip proteins: more than just CDKs inhibitors. Genes Dev 18:851–855

    Article  CAS  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  CAS  Google Scholar 

  • Fitton JH (2011) Therapies from fucoidan; multifunctional marine polymers. Mar Drugs 9:1731–1760

    Article  CAS  Google Scholar 

  • Forde JE, Dale TC (2007) Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci 64:1930–1944

    Article  CAS  Google Scholar 

  • Garnick MB (1997) Hormonal therapy in the management of prostate cancer: from Huggins to the present. Urology 49:5–15

    Article  CAS  Google Scholar 

  • Hakomori S (1964) A rapid permethylation of glycolipid, and polysaccharide catalyzed by methylsulfinyl carbanion in dimethyl sulfoxide. J Biochem 55:205–208

    CAS  PubMed  Google Scholar 

  • Hanks GE (1996) Long-term control of prostate cancer with radiation. Past, present, and future. Urol Clin North Am 23:605–616

    Article  CAS  Google Scholar 

  • Hemmingson JA, Falshaw R, Furneaux R, Thompson K (2006) Structure and antiviral activity of the galactofucan sulfates extracted from Undaria pinnatifida (Phaeophyta). J Appl Phycol 18:185–193

    Article  CAS  Google Scholar 

  • Hsu HY, Lin TY, Hwang PA, Tseng LM, Chen RH, Tsao SM, Hsu J (2013) Fucoidan induces changes in the epithelial to mesenchymal transition and decreases metastasis by enhancing ubiquitin-dependent TGFbeta receptor degradation in breast cancer. Carcinogenesis 34:874–884

    Article  CAS  Google Scholar 

  • Hsu HY, Lin TY, Wu YC, Tsao SM, Hwang PA, Shih YW, Hsu J (2014) Fucoidan inhibition of lung cancer in vivo and in vitro: role of the Smurf2-dependent ubiquitin proteasome pathway in TGFbeta receptor degradation. Oncotarget 5:7870–7885

    PubMed  PubMed Central  Google Scholar 

  • Huynh H, Nguyen TH, Panasci L, Do P (2004) 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) inhibits prostate carcinoma cell growth via p53-dependent and p53-independent pathways. Cancer 101:2881–2891

    Article  CAS  Google Scholar 

  • Jansson PE, Kenne L, Liedgren H, Lindberg B, Lonngren J (1976) A practical guide to the methylation: analysis of carbohydrates. Chem Commun Stockholm Univ 8:1–74

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  Google Scholar 

  • Kim WJ, Choi JW, Jang WJ, Kang YS, Lee CW, Synytsya A, Park YI (2017) Low-molecular weight mannogalactofucans prevent herpes simplex virus type 1 infection via activation of Toll-like receptor 2. Int J Biol Macromol 103:286–293

    Article  CAS  Google Scholar 

  • Kim WJ, Kim SM, Kim HG, Oh HR, Lee KB, Lee YK, Park YI (2007) Purification and anticoagulant activity of a fucoidan from Korean Undaria pinnatifida sporophyll. Algae 22:247–252

    Article  Google Scholar 

  • Kim WJ, Kim SM, Lee YH, Kim HG, Kim HK, Moon SH, Suh HH, Jang KH, Park YI (2008) Isolation and characterization of marine bacterial strain degrading fucoidan from Korean Undaria pinnatifida sporophylls. J Microbiol Biotechnol 18:616–623

    CAS  PubMed  Google Scholar 

  • Kim WJ, Koo YK, Jung MK, Moon HR, Kim SM, Synytsya A, Yun-Choi HS, Kim YS, Park JK, Park YI (2010) Anticoagulating activities of low-molecular weight fuco-oligosaccharides prepared by enzymatic digestion of fucoidan from the sporophyll of Korean Undaria pinnatifida. Arch Pharm Res 33:125–131

    Article  CAS  Google Scholar 

  • Kim WJ, Park JW, Park JK, Choi DJ, Park YI (2015) Purification and characterization of a fucoidanase (FNase S) from a marine bacterium Sphingomonas paucimobilis PF-1. Mar Drugs 13:4398–4417

    Article  CAS  Google Scholar 

  • Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136

    Article  CAS  Google Scholar 

  • Kwak JY (2014) Fucoidan as a marine anticancer agent in preclinical development. Mar Drugs 12:851–870

    Article  CAS  Google Scholar 

  • Lake AC, Vassy R, Di Benedetto M, Lavigne D, Le Visage C, Perret GY, Letourneur D (2006) Low molecular weight fucoidan increases VEGF165-induced endothelial cell migration by enhancing VEGF165 binding to VEGFR-2 and NRP1. J Biol Chem 281:37844–37852

    Article  CAS  Google Scholar 

  • Lebel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231

    Article  CAS  Google Scholar 

  • Lee J, Lee S, Kim SL, Choi JW, Seo JY, Choi DJ, Park YI (2014) Corn silk maysin induces apoptotic cell death in PC-3 prostate cancer cells via mitochondria-dependent pathway. Life Sci 119:47–55

    Article  CAS  Google Scholar 

  • Li J, Xing M, Zhu M, Wang X, Wang M, Zhou S, Li N, Wu R, Zhou M (2008) Glycogen synthase kinase 3beta induces apoptosis in cancer cells through increase of survivin nuclear localization. Cancer Lett 272:91–101

    Article  CAS  Google Scholar 

  • Lin T, Ding Z, Li N, Xu J, Luo G, Liu J, Shen J (2011) Seleno-cyclodextrin sensitises human breast cancer cells to TRAIL-induced apoptosis through DR5 induction and NF-kappaB suppression. Eur J Cancer 47:1890–1907

    Article  CAS  Google Scholar 

  • Luyt CE, Meddahi-Pelle A, Ho-Tin-Noe B, Colliec-Jouault S, Guezennec J, Louedec L, Prats H, Jacob MP, Osborne-Pellegrin M, Letourneur D, Michel JB (2003) Low-molecular-weight fucoidan promotes therapeutic revascularization in a rat model of critical hindlimb ischemia. J Pharmacol Exp Ther 305:24–30

    Article  CAS  Google Scholar 

  • Maruyama H, Tamauchi H, Iizuka M, Nakano T (2006) The role of NK cells in antitumor activity of dietary fucoidan from Undaria pinnatifida sporophylls (Mekabu). Planta Med 72:1415–1417

    Article  CAS  Google Scholar 

  • Patel S (2012) Therapeutic importance of sulfated polysaccharides from seaweeds: updating the recent findings. 3 Biotech 2:171–185

    Article  Google Scholar 

  • Robertson BW, Chellaiah MA (2010) Osteopontin induces beta-catenin signaling through activation of Akt in prostate cancer cells. Exp Cell Res 316:1–11

    Article  CAS  Google Scholar 

  • Shankar S, Chen Q, Sarva K, Siddiqui I, Srivastava RK (2007) Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: molecular mechanisms of apoptosis, migration and angiogenesis. J Mol Signal 2:10

    Article  Google Scholar 

  • Shankar S, Chen X, Srivastava RK (2005) Effects of sequential treatments with chemotherapeutic drugs followed by TRAIL on prostate cancer in vitro and in vivo. Prostate 62:165–186

    Article  CAS  Google Scholar 

  • Shankar S, Singh TR, Srivastava RK (2004) Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: intracellular mechanisms. Prostate 61:35–49

    Article  CAS  Google Scholar 

  • Shukla S, Maclennan GT, Flask CA, Fu P, Mishra A, Resnick MI, Gupta S (2007) Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. Cancer Res 67:6925–6935

    Article  CAS  Google Scholar 

  • Srivastava RK (2000) Intracellular mechanisms of TRAIL and its role in cancer therapy. Mol Cell Biol Res Commun 4:67–75

    Article  CAS  Google Scholar 

  • Srivastava RK (2001) TRAIL/Apo-2L: mechanisms and clinical applications in cancer. Neoplasia 3:535–546

    Article  CAS  Google Scholar 

  • Syed V, Mak P, Du C, Balaji KC (2008) Beta-catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E-cadherin and protein kinase D1. J Cell Biochem 104:82–95

    Article  CAS  Google Scholar 

  • Synytsya A, Bleha R, Synytsya A, Pohl R, Hayashi K, Yoshinaga K, Nakano T, Hayashi T (2014) Mekabu fucoidan: structural complexity and defensive effects against avian influenza A viruses. Carbohydr Polym 111:633–644

    Article  CAS  Google Scholar 

  • Synytsya A, Choi DJ, Pohl R, Na YS, Capek P, Lattova E, Taubner T, Choi JW, Lee CW, Park JK, Kim WJ, Kim SM, Lee J, Park YI (2015) Structural features and anti-coagulant activity of the sulphated polysaccharide SPS-CF from a green alga Capsosiphon fulvescens. Mar Biotechnol (NY) 17:718–735

    Article  CAS  Google Scholar 

  • Synytsya A, Kim W-J, Kim S-M, Pohl R, Synytsya A, Kvasnička F, Čopíková J, Il Park Y (2010) Structure and antitumour activity of fucoidan isolated from sporophyll of Korean brown seaweed Undaria pinnatifida. Carbohydr Polym 81:41–48

    Article  CAS  Google Scholar 

  • Tako M, Nakada T, Hongou F (1999) Chemical characterization of fucoidan from commercially cultured Nemacystus decipiens (Itomozuku). Biosci Biotechnol Biochem 63:1813–1815

    Article  CAS  Google Scholar 

  • Xue M, Ge Y, Zhang J, Liu Y, Wang Q, Hou L, Zheng Z (2013) Fucoidan inhibited 4T1 mouse breast cancer cell growth in vivo and in vitro via downregulation of Wnt/beta-catenin signaling. Nutr Cancer 65:460–468

    Article  CAS  Google Scholar 

  • Xue M, Ge Y, Zhang J, Wang Q, Hou L, Liu Y, Sun L, Li Q (2012) Anticancer properties and mechanisms of fucoidan on mouse breast cancer in vitro and in vivo. PLoS One 7:e43483

    Article  CAS  Google Scholar 

  • Yang C, Chung D, Shin IS, Lee H, Kim J, Lee Y, You S (2008) Effects of molecular weight and hydrolysis conditions on anticancer activity of fucoidans from sporophyll of Undaria pinnatifida. Int J Biol Macromol 43:433–437

    Article  CAS  Google Scholar 

  • Yang G, Zhang Q, Kong Y, Xie B, Gao M, Tao Y, Xu H, Zhan F, Dai B, Shi J, Wu X (2015) Antitumor activity of fucoidan against diffuse large B cell lymphoma in vitro and in vivo. Acta Biochim Biophys Sin Shanghai 47:925–931

    Article  CAS  Google Scholar 

  • Zhang Z, Teruya K, Eto H, Shirahata S (2011) Fucoidan extract induces apoptosis in MCF-7 cells via a mechanism involving the ROS-dependent JNK activation and mitochondria-mediated pathways. PLoS One 6:e27441

    Article  CAS  Google Scholar 

  • Zhang Z, Teruya K, Eto H, Shirahata S (2013) Induction of apoptosis by low-molecular-weight fucoidan through calcium- and caspase-dependent mitochondrial pathways in MDA-MB-231 breast cancer cells. Biosci Biotechnol Biochem 77:235–242

    Article  CAS  Google Scholar 

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Funding

This work was supported by a grant from the Gyeonggi-do GRRC programme (Project No. 2017-B01) and partly by the 2018 Research Fund of The Catholic University of Korea, for which the authors are thankful. The financial supports by the Basic Science Research Program (No. 2018R1A6A1A03023584) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education and the projects of Slovak Grant Agency VEGA (grant no. 2/0051/18) and Ministry of Industry and Trade of the Czech Republic (MPO – TRIO project ALGAL FOODS – FV10155) are also greatly acknowledged.

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  1. Jisun Lee and Seul Lee contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, South Korea

    Jisun Lee, Seul Lee, Chang Won Lee, Ji Won Choi, Sarang Cho & Yong Il Park

  2. Department of Carbohydrate Chemistry and Technology, University of Chemical Technology in Prague, Technická 5, 166 28, Prague 6, Czech Republic

    Andriy Synytsya

  3. Institute of Chemistry, Centre for Glycomics, Slovak Academy of Sciences, Dúbravská cesta 9, 845 38, Bratislava, Slovakia

    Peter Capek

  4. Biocenter, Gyeonggido Business and Science Accelerator (GBSA), Suwon, Gyeonggi-do, 16229, South Korea

    Woo Jung Kim

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  1. Jisun Lee
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Correspondence to Yong Il Park.

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The animal protocol (Approval number 2014-032) was approved by the Institutional Animal Care and Use Committee of The Catholic University of Korea.

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Lee, J., Lee, S., Synytsya, A. et al. Low Molecular Weight Mannogalactofucans Derived from Undaria pinnatifida Induce Apoptotic Death of Human Prostate Cancer Cells In Vitro and In Vivo. Mar Biotechnol 20, 813–828 (2018). https://doi.org/10.1007/s10126-018-9851-3

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