title: Improving fascin inhibitors to block tumor cell migration and metastasis.
abstract: Tumor metastasis is the major cause of mortality of cancer patients, being responsible for ∼90% of all cancer deaths. One of the key steps during tumor metastasis is tumor cell migration which requires actin cytoskeletal reorganization. Among the critical actin cytoskeletal protrusion structures are antenna-like filopodia. Fascin protein is the main actin-bundling protein in filopodia. Here we report the development of fascin-specific small-molecules that inhibit the interaction between fascin and actin. These inhibitors block the in vitro actin-binding and actin-bundling activities of fascin, tumor cell migration and tumor metastasis in mouse models. Mechanistically, these inhibitors likely occupy one of the actin-binding sites, reduce the binding of actin filaments, and thus lead to the inhibition of the bundling activity of fascin. At the cellular level, these inhibitors impair actin cytoskeletal reorganization. Our data indicate that target-specific anti-fascin agents will have great potential for treating metastatic tumors.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China; Department of Physiology and Biophysics, Cornell University, Weill Medical College, New York, NY 10065, USA.
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Physiology and Biophysics, Cornell University, Weill Medical College, New York, NY 10065, USA.
authors.forename: Jianyun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Physiology and Biophysics, Cornell University, Weill Medical College, New York, NY 10065, USA.
authors.forename: Bingqian
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Physiology and Biophysics, Cornell University, Weill Medical College, New York, NY 10065, USA.
authors.forename: Bowen
authors.initials: B
authors.lastname: Xing
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Bordeleau
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Reinhart-King
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, Cornell University, Weill Medical College, New York, NY 10065, USA.
authors.forename: J Jillian
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, Cornell University, Weill Medical College, New York, NY 10065, USA. Electronic address: xyhuang@med.cornell.edu.
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Huang
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009362:Neoplasm Metastasis; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C502658:FSCN1 protein, human; D008840:Microfilament Proteins; D054852:Small Molecule Libraries
keywords: Fascin; Inhibitors; Metastasis