Migrastatin analogues target fascin to block tumour metastasis.
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.
Chen
Lin
L
Department of Physiology, Cornell University Weill Medical College, New York, New York 10065, USA.
Yang
Shengyu
S
Jakoncic
Jean
J
Zhang
J Jillian
JJ
Huang
Xin-Yun
XY
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
D000199:Actins; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018942:Macrolides; D008840:Microfilament Proteins; D010881:Piperidones; C418199:migrastatin; C020324:fascin
Lung Cancer. 2003 Nov;42(2):203-13
14568688
Nature. 2005 Jul 28;436(7050):518-24
16049480
Nature. 2002 Jan 31;415(6871):530-6
11823860
Clin Cancer Res. 2006 Mar 1;12(5):1533-9
16533778
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2184-95
15572771
Genetics. 1996 May;143(1):249-58
8722779
Cancer Res. 2007 Jul 15;67(14):6844-53
17638895
Eur J Nucl Med Mol Imaging. 2004 May;31(5):740-51
15014901
J Biol Chem. 1985 Apr 25;260(8):5087-97
3886649
Am J Clin Pathol. 2002 Jul;118(1):52-9
12109856
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
15572765
J Cell Biol. 2006 Sep 11;174(6):863-75
16966425
Clin Cancer Res. 2005 Jan 1;11(1):186-92
15671545
Clin Cancer Res. 2008 Apr 1;14(7):1938-46
18381931
Dev Cell. 2006 Jun;10(6):707-18
16740474
Cancer Cell. 2009 Feb 3;15(2):124-34
19185847
Curr Opin Cell Biol. 2004 Oct;16(5):590-6
15363811
J Am Chem Soc. 2004 Feb 4;126(4):1038-40
14746469
Urology. 2006 Sep;68(3):518-22
16979727
Bioorg Med Chem Lett. 2008 Nov 15;18(22):5951-4
18684620
Oncology. 2004;67(3-4):262-70
15557788
J Mol Biol. 1978 Oct 25;125(2):207-24
731692
J Antibiot (Tokyo). 2002 Feb;55(2):141-6
12002995
J Am Chem Soc. 2004 Sep 15;126(36):11326-37
15355116
J Virol. 1994 Nov;68(11):7320-8
7933116
Int J Biochem Cell Biol. 2005 Sep;37(9):1787-804
16002322
J Biol Chem. 2005 Jul 22;280(29):27130-7
15911622
Br J Cancer. 2000 Oct;83(7):870-3
10970687
J Cell Biol. 2003 Mar 17;160(6):951-62
12642617
J Antibiot (Tokyo). 2000 Oct;53(10):1228-30
11132973
Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3772-6
15728385
J Clin Invest. 2005 Jan;115(1):44-55
15630443
Mol Biol Cell. 2007 Nov;18(11):4591-602
17855511
Oncogene. 2006 Jun 29;25(28):3994-4008
16491124
Cell. 1979 Jun;17(2):285-93
378407
J Biol Chem. 1997 Jan 24;272(4):2527-33
8999969