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Migrastatin analogues target fascin to block tumour metastasis

A Corrigendum to this article was published on 20 July 2011

Abstract

Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces1,2, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis3,4,5,6. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

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Figure 1: Identification of fascin as a macroketone target.
Figure 2: X-ray crystal structures of fascin and of the complex of fascin and macroketone.
Figure 3: Macroketone-binding site overlaps with one of the actin-binding sites.
Figure 4: Fascin His 474 mutation renders tumour cell migration, invasion and metastasis resistant to macroketone.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The coordinates and structure factors of crystal structures of fascin and the fascin–macroketone complex have been deposited in the Protein Data Bank under accession numbers 3LLP and 3LNA, respectively.

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Acknowledgements

J.J.Z. and X.Y.H. dedicate this paper to the memory of Yonghong Zhang, who died of cancer on 12 September 2009. We are grateful to W. Gerald (deceased) at Memorial Sloan-Kettering Cancer Center for letting us examine his DNA microarray data on human breast tumour samples for the fascin expression. We thank S. Almo for the fascin plasmid; S. Danishefsky and colleagues for the biotin-conjugated macroketone used in the initial exploration of the conditions for protein purification; members of the J. Massagué laboratory for teaching the use of the IVIS Imaging system; the personnel at the beamlines X6A and X4C of the National Synchrotron Light Source for the beamtime and for assistance; and D. Eliezer, T. Maack, L. Palmer, H. Wu and members of our laboratory for critically reading the manuscript. We thank S. Almo and his colleagues, H. Wu and J. Wu, for help with the crystallization experiments. This work was supported by grants from the National Institutes of Health (CA136837) and the Department of Defense (W81XWH-06-1-0362).

Author Contributions L.C., S.Y., J.J.Z. and X.Y.H. conceived the project. L.C. and S.Y. performed the experiments. S.Y. and J.J. determined the structures. L.C., S.Y., J.J.Z. and X.Y.H. analysed the data and wrote the paper.

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Correspondence to Xin-Yun Huang.

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This file contains Supplementary Figures 1-11with legends and Supplementary Tables S1-S4. (PDF 7434 kb)

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Chen, L., Yang, S., Jakoncic, J. et al. Migrastatin analogues target fascin to block tumour metastasis. Nature 464, 1062–1066 (2010). https://doi.org/10.1038/nature08978

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