Migrastatin analogues target fascin to block tumour metastasis

Lin Chen; Shengyu Yang; Jean Jakoncic; J. Jillian Zhang; Xin Yun Huang

doi:10.1038/nature08978

Migrastatin analogues target fascin to block tumour metastasis

Lin Chen
, Shengyu Yang
, Jean Jakoncic
, J. Jillian Zhang
, Xin Yun Huang

Research output: Contribution to journal › Article › peer-review

250 Scopus citations

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 Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. 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.

Original language	English (US)
Pages (from-to)	1062-1066
Number of pages	5
Journal	Nature
Volume	464
Issue number	7291
DOIs	https://doi.org/10.1038/nature08978
State	Published - Apr 15 2010

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

General

Access to Document

10.1038/nature08978

Cite this

@article{95883452f1f941a1bdb610119cfe1dca,

title = "Migrastatin analogues target fascin to block tumour metastasis",

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 Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. 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.",

author = "Lin Chen and Shengyu Yang and Jean Jakoncic and Zhang, \{J. Jillian\} and Huang, \{Xin Yun\}",

note = "Funding Information: 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. Massagu{\'e} 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).",

year = "2010",

month = apr,

day = "15",

doi = "10.1038/nature08978",

language = "English (US)",

volume = "464",

pages = "1062--1066",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7291",

}

TY - JOUR

T1 - Migrastatin analogues target fascin to block tumour metastasis

AU - Chen, Lin

AU - Yang, Shengyu

AU - Jakoncic, Jean

AU - Zhang, J. Jillian

AU - Huang, Xin Yun

N1 - Funding Information: 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).

PY - 2010/4/15

Y1 - 2010/4/15

N2 - 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 Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. 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.

AB - 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 Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. 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.

UR - https://www.scopus.com/pages/publications/77951116071

UR - https://www.scopus.com/pages/publications/77951116071#tab=citedBy

U2 - 10.1038/nature08978

DO - 10.1038/nature08978

M3 - Article

C2 - 20393565

AN - SCOPUS:77951116071

SN - 0028-0836

VL - 464

SP - 1062

EP - 1066

JO - Nature

JF - Nature

IS - 7291

ER -

Migrastatin analogues target fascin to block tumour metastasis

Abstract

UN SDGs

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this