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.
authors.affiliation: Department of Physiology, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Shengyu
authors.initials: S
authors.lastname: Yang
authors.forename: Jean
authors.initials: J
authors.lastname: Jakoncic
authors.forename: J Jillian
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Huang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D010881:Piperidones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018942:Macrolides; D008840:Microfilament Proteins; D010881:Piperidones; C418199:migrastatin; C020324:fascin
references.citation: Lung Cancer. 2003 Nov;42(2):203-13
references.pmid: 14568688
references.citation: Nature. 2005 Jul 28;436(7050):518-24
references.pmid: 16049480
references.citation: Nature. 2002 Jan 31;415(6871):530-6
references.pmid: 11823860
references.citation: Clin Cancer Res. 2006 Mar 1;12(5):1533-9
references.pmid: 16533778
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2184-95
references.pmid: 15572771
references.citation: Genetics. 1996 May;143(1):249-58
references.pmid: 8722779
references.citation: Cancer Res. 2007 Jul 15;67(14):6844-53
references.pmid: 17638895
references.citation: Eur J Nucl Med Mol Imaging. 2004 May;31(5):740-51
references.pmid: 15014901
references.citation: J Biol Chem. 1985 Apr 25;260(8):5087-97
references.pmid: 3886649
references.citation: Am J Clin Pathol. 2002 Jul;118(1):52-9
references.pmid: 12109856
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: J Cell Biol. 2006 Sep 11;174(6):863-75
references.pmid: 16966425
references.citation: Clin Cancer Res. 2005 Jan 1;11(1):186-92
references.pmid: 15671545
references.citation: Clin Cancer Res. 2008 Apr 1;14(7):1938-46
references.pmid: 18381931
references.citation: Dev Cell. 2006 Jun;10(6):707-18
references.pmid: 16740474
references.citation: Cancer Cell. 2009 Feb 3;15(2):124-34
references.pmid: 19185847
references.citation: Curr Opin Cell Biol. 2004 Oct;16(5):590-6
references.pmid: 15363811
references.citation: J Am Chem Soc. 2004 Feb 4;126(4):1038-40
references.pmid: 14746469
references.citation: Urology. 2006 Sep;68(3):518-22
references.pmid: 16979727
references.citation: Bioorg Med Chem Lett. 2008 Nov 15;18(22):5951-4
references.pmid: 18684620
references.citation: Oncology. 2004;67(3-4):262-70
references.pmid: 15557788
references.citation: J Mol Biol. 1978 Oct 25;125(2):207-24
references.pmid: 731692
references.citation: J Antibiot (Tokyo). 2002 Feb;55(2):141-6
references.pmid: 12002995
references.citation: J Am Chem Soc. 2004 Sep 15;126(36):11326-37
references.pmid: 15355116
references.citation: J Virol. 1994 Nov;68(11):7320-8
references.pmid: 7933116
references.citation: Int J Biochem Cell Biol. 2005 Sep;37(9):1787-804
references.pmid: 16002322
references.citation: J Biol Chem. 2005 Jul 22;280(29):27130-7
references.pmid: 15911622
references.citation: Br J Cancer. 2000 Oct;83(7):870-3
references.pmid: 10970687
references.citation: J Cell Biol. 2003 Mar 17;160(6):951-62
references.pmid: 12642617
references.citation: J Antibiot (Tokyo). 2000 Oct;53(10):1228-30
references.pmid: 11132973
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3772-6
references.pmid: 15728385
references.citation: J Clin Invest. 2005 Jan;115(1):44-55
references.pmid: 15630443
references.citation: Mol Biol Cell. 2007 Nov;18(11):4591-602
references.pmid: 17855511
references.citation: Oncogene. 2006 Jun 29;25(28):3994-4008
references.pmid: 16491124
references.citation: Cell. 1979 Jun;17(2):285-93
references.pmid: 378407
references.citation: J Biol Chem. 1997 Jan 24;272(4):2527-33
references.pmid: 8999969