Skip to main content

Advertisement

SpringerLink
Log in

Marine algal carotenoids inhibit angiogenesis by down-regulating FGF-2-mediated intracellular signals in vascular endothelial cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Discovery of natural compounds as effective angiogenesis inhibitors has become an important approach in the prevention of cancer. We previously demonstrated the anti-angiogenic potential of two marine algal carotenoids, fucoxanthin and siphonaxanthin. In this study, we evaluated the molecular mechanisms of the anti-angiogenic activity of those two carotenoids using human umbilical vein endothelial cells. This study showed that both fucoxanthin and siphonaxanthin suppress the mRNA expression of fibroblast growth factor 2 (FGF-2) and its receptor (FGFR-1) as well as their trans-activation factor, EGR-1. But, the mRNA expression of VEGFR-2 did not show significant effect by those two carotenoids. Further, those two marine algal carotenoids down-regulate the phosphorylation of FGF-2-mediated intracellular signaling proteins such as ERK1/2 and Akt. Inhibition of FGF-2-mediated intracellular signaling proteins by those carotenoids represses the migration of endothelial cells as well as their differentiation into tube-like structures on Matrigel. These results demonstrate for the first time the possible molecular mechanism underlying the anti-angiogenic effects of fucoxanthin and siphonaxanthin and suggest that these effects are due to the down-regulation of signal transduction by FGFR-1. Our findings imply a new insight into the novel bio-functional property of marine algal carotenoids which should improve current anti-angiogenic therapies in the treatment of cancer and other pro-angiogenic diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931–10934

    CAS  PubMed  Google Scholar 

  2. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257

    Article  CAS  PubMed  Google Scholar 

  3. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–30

    Article  CAS  PubMed  Google Scholar 

  4. Virmani R, Kolodgie FD, Burke AP, Fin AV, Gold HK, Tulenko TN, Wrenn SP, Narula J (2005) Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Atheroscler Thromb Vasc Biol 25:2054–2061

    Article  CAS  Google Scholar 

  5. Qian DZ, Wang X, Kachhap SK, Kato Y, Wei Y, Zhang L, Atadja P, Pili R (2004) The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater anti-tumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 64:6626–6634

    Article  CAS  PubMed  Google Scholar 

  6. Hicklin DJ, Ellis LM (2005) Role of vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027

    Article  CAS  PubMed  Google Scholar 

  7. Folkman J (2002) Looking for a good endothelial address. Cancer Cell 1:113–115

    Article  CAS  PubMed  Google Scholar 

  8. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309

    Article  CAS  PubMed  Google Scholar 

  9. Kerbel RS (2005) Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy revealed. Cancer Cell 8:269–271

    Article  CAS  PubMed  Google Scholar 

  10. Ferrara N (1999) Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol 237:1–30

    CAS  PubMed  Google Scholar 

  11. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    Article  CAS  PubMed  Google Scholar 

  12. Vinals F, Pouyssegur J (2001) Transforming growth factor β1 (TGF-β1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-α signaling. Mol Cell Biol 21:7218–7230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974

    Article  CAS  PubMed  Google Scholar 

  14. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery. Nat Rev 6:273–286

    CAS  Google Scholar 

  15. Garber K (2002) Angiogenesis inhibitors suffer new setback. Nat Biotechnol 20:1067–1068

    Article  CAS  PubMed  Google Scholar 

  16. Kamba T, McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96:1788–1795

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Albini A, Noonan DM, Ferrari N (2007) Molecular pathways for cancer angioprevention. Clin Cancer Res 13:4320–4325

    Article  CAS  PubMed  Google Scholar 

  18. Cao Y (2004) Antiangiogenic cancer therapy. Semin Cancer Biol 14:139–145

    Article  CAS  PubMed  Google Scholar 

  19. Sagar SM, Yance D, Wong RK (2006) Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer. Curr Oncol 13:14–26

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Sugawara T, Matsubara K, Akagi R, Mori M, Hirata T (2006) Antiangiogenic activity of brown algae fucoxanthin and its deacetylated product, fucoxanthinol. J Agric Food Chem 54:9805–9810

    Article  CAS  PubMed  Google Scholar 

  21. Ganesan P, Matsubara K, Ohkubo T, Tanaka Y, Noda K, Sugawara T, Hirata T (2010) Anti-angiogenic effect of siphonaxanthin from green alga, Codium fragile. Phytomedicine 17:1140–1144

    Article  CAS  PubMed  Google Scholar 

  22. Sugawara T, Yamashita K, Asai A, Nagao A, Shiraishi T, Imai I, Hirata T (2009) Esterification of xanthophylls by human intestinal Caco-2 cells. Arch Biochem Biophys 483:205–212

    Article  CAS  PubMed  Google Scholar 

  23. Ganesan P, Noda K, Manabe Y, Ohkubo T, Tanaka Y, Maoka T, Sugawara T, Hirata T (2011) Siphonaxanthin, a marine algal carotenoids from green algae, effectively induces apoptosis in human leukemia (HL-60) cells. Biochim Biophys Acta 1810:497–503

    Article  CAS  PubMed  Google Scholar 

  24. Matsubara K, Xue C, Zhao X, Mori M, Sugawara T, Hirata T (2005) Effects of middle molecular weight fucoidans on in vitro and ex vivo angiogenesis of endothelial cells. Int J Mol Med 15:695–699

    CAS  PubMed  Google Scholar 

  25. Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M (1984) Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 223:1296–1299

    Article  CAS  PubMed  Google Scholar 

  26. Cross MJ, Claesson-Welsh L (2001) FGF and VEGF function in angiogenesis: signaling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci 22:201–207

    Article  CAS  PubMed  Google Scholar 

  27. Wang D, Mayo MW Jr, Balswin AS (1997) Basic fibroblast growth factor transcriptional autoregulation requires Egr-1. Oncogene 14:2291–2299

    Article  CAS  PubMed  Google Scholar 

  28. Santiago FS, Lowe HC, Day FL, Chesterman CN, Khachigian LM (1999) Early growth response factor-1 induction by injury is triggered by release and paracrine activation by fibroblast growth factor-2. Am J Pathol 154:937–944

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Montesano R, Orci L, Vassalli P (1983) In vitro rapid organization of endothelial cells into capillary-like networks is promoted by collagen matrices. J Cell Biol 97:1648–1652

    Article  CAS  PubMed  Google Scholar 

  30. Dailey L, Ambrosetti D, Mansukhani A, Basilico C (2005) Mechanisms underlying differential responses to FGF-signaling. Cytokine Growth Factor Rev 16:233–247

    Article  CAS  PubMed  Google Scholar 

  31. Feng X, Ofstad W, Hawkins D (2010) Antiangiogenesis therapy: a new strategy for cancer treatment. US Pharm 35:4–9

    Google Scholar 

  32. Al-Jamal KT, Al-Jamal WT, Akerman S, Podesta JE, Yilmazer A, Turton JA, Bianco A, Vargesson N, Kanthou C, Florence AT, Tozer GM, Kostarelos K (2010) Systemic anti-angiogenic activity of cationic poly-l-lysine dendrimer delays tumor growth. Proc Natl Acad Sci USA 107:3966–3971

    Article  PubMed Central  PubMed  Google Scholar 

  33. Turner N, Grose R (2010) Fibroblast growth factor signaling: from development to cancer. Nat Rev 10:116–129

    Article  CAS  Google Scholar 

  34. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  35. Fahmy RG, Dass CR, Sun L, Chesterman CN, Khachigian LM (2003) Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med 9:1026–1032

    Article  CAS  PubMed  Google Scholar 

  36. Altomare DA, Testa JR (2005) Perturbation of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464

    Article  CAS  PubMed  Google Scholar 

  37. Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139–149

    Article  CAS  PubMed  Google Scholar 

  38. Hood JD, Frausto R, Kiosses WB, Schwartz MA, Cheresh DA (2003) Differential αv integrin-mediated Ras–ERK signaling during two pathways of angiogenesis. J Cell Biol 162:933–943

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Eliceiri BP, Klemke R, Strömblad S, Cheresh DA (1998) Integrin αvβ3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. J Cell Biol 140:1255–1263

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signaling pathway in human malignancy. Cell Signal 14:381–395

    Article  CAS  PubMed  Google Scholar 

  41. Kok TW, Yue PYK, Mak NK, Fan TPD, Liu L, Wong RNS (2005) The anti-angiogenic effect of sinomenine. Angiogenesis 8:3–12

    Article  CAS  PubMed  Google Scholar 

  42. Hussain S, Slevin M, Matou S, Ahmed N, Choudhary MI, Ranjit R, West D, Gaffney J (2008) Anti-angiogenic activity of sesterterpenes: natural product inhibitors of FGF-2-induced angiogenesis. Angiogenesis 11:245–256

    Article  CAS  PubMed  Google Scholar 

  43. Peng C, Pan S, Lee K, Bastow KF, Tend C (2008) Molecular mechanism of the inhibitory effect of KS-5 on FGF-2-induced angiogenesis in vitro and in vivo. Cancer Lett 263:114–121

    Article  CAS  PubMed  Google Scholar 

  44. Miyazawa T, Shibata A, Sookwong P, Kawakami Y, Eitsuka T, Asai A, Oikawa S, Nakagawa K (2009) Anti-angiogenic and anti-cancer potential of unsaturated vitamin E (tocotrienol). J Nutr Biochem 20:79–86

    Article  CAS  PubMed  Google Scholar 

  45. Sugawara T, Baskaran V, Tsuzuki W, Nagao A (2002) Brown algae fucoxanthin is hydrolyzed to fucoxanthinol during absorption by Caco-2 human intestinal cells and mice. J Nutr 132:946–951

    CAS  PubMed  Google Scholar 

  46. Asai A, Sugawara T, Ono H, Nagao A (2004) Biotransformation of fucoxanthinol to amarouciaxanthin A in mice and HepG2 cells: formation and cytotoxicity of fucoxanthin metabolites. Drug Metab Dispos 32:205–211

    Article  CAS  PubMed  Google Scholar 

  47. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Government of Japan, the Kieikai Research Foundation and a Grant-in-Aid for Scientific Research (B) (23380124), Japan.

Conflict of interest

The authors declare no potential conflict of interest.

Author information

Authors and Affiliations

  1. Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan

    Ponesakki Ganesan, Tatsuya Sugawara & Takashi Hirata

  2. SRM Research Institute, SRM University, Kattankulathur, 603 203, Tamilnadu, India

    Ponesakki Ganesan

  3. Department of Human Life Sciences Education, Graduate School of Education, Hiroshima University, Higashi, Hiroshima, 739-8524, Japan

    Kiminori Matsubara

Authors
  1. Ponesakki Ganesan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kiminori Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsuya Sugawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takashi Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatsuya Sugawara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ganesan, P., Matsubara, K., Sugawara, T. et al. Marine algal carotenoids inhibit angiogenesis by down-regulating FGF-2-mediated intracellular signals in vascular endothelial cells. Mol Cell Biochem 380, 1–9 (2013). https://doi.org/10.1007/s11010-013-1651-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-013-1651-5

Keywords

Search

Navigation