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Biochem. J. (2007) 406 (49–55) (Printed in Great Britain)

Polyphosphate blocks tumour metastasis via anti-angiogenic activity

Kyu Yeon HAN*1, Bok Sil HONG*1, Yae Jin YOON†, Chang Min YOON*, Yoon-Keun KIM*, Young-Guen KWON‡ and Yong Song GHO*2

*Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea, †School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea, and ‡Department of Biochemistry, College of Natural Sciences, Yonsei University, Seoul 120-752, Republic of Korea

PolyP (inorganic polyphosphate) is a linear polymer of many tens or hundreds of orthophosphate residues found in a wide range of organisms, including bacteria, fungi, insects, plants and vertebrates. Despite its wide distribution in mammalian tissues and plasma, the biological functions of polyP on tumour metastasis and angiogenesis have not been previously examined. In the present study, we have shown that polyP effectively blocked in vivo pulmonary metastasis of B16BL6 cells by suppression of neovascularization, whereas it did not affect proliferation or adhesion to extracellular matrix proteins. PolyP not only inhibited bFGF (basic fibroblast growth factor)-induced proliferation and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) activation of human endothelial cells, but also blocked the binding of bFGF to its cognate cell-surface receptor. Furthermore, polyP inhibited bFGF-induced in vitro and in vivo angiogenesis, suggesting that polyP possesses an anti-angiogenic activity. Since neovascularization is essential for tumour metastasis, our present findings clearly indicate that polyP has an in vivo anti-metastatic activity via its anti-angiogenic activity. Taken together with the fact that angiogenesis occurs under various normal and pathological conditions, our observations suggest that endogenous polyP may play a critical role during embryonic development, wound healing and inflammation, as well as in the progress of pathological diseases such as rheumatoid arthritis and cancer.

Key words: angiogenesis, basic fibroblast growth factor (bFGF), endothelial cell, polyanion, inorganic polyphosphate (polyP), tumour metastasis.

Abbreviations used: bFGF, basic fibroblast growth factor; CAM, chorioallantoic membrane; ERK, extracellular-signal-regulated kinase; FBS, foetal bovine serum; Fc, fragment of IgG1; FGF R1, FGF receptor 1; FGF R1–Fc, a soluble chimaera protein consisting of the extracellular domain of the human FGF R1a and Fc region of human IgG1; HUVEC, human umbilical vein endothelial cell; MAPK, mitogen-activated protein kinase; MEM, minimal essential medium; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; PBST, PBS+0.05% Tween 20; polyP, inorganic polyphosphate.

¹These authors contributed equally to this work.

²To whom correspondence should be addressed (email ysgho@postech.ac.kr).

Received 12 October 2006/20 April 2007; accepted 10 May 2007

Published as BJ Immediate Publication 10 May 2007, doi:10.1042/BJ20061542

© The Authors Journal compilation © 2007 Biochemical Society

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