A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions.
Medina-Franco, José L.
Orlowski, Mikayla L.
Maggiora, Gerald M.
Restifo, Linda L.
AffiliationDepartment of Neuroscience, University of Arizona, Tucson, AZ
Torrey Pines Institute for Molecular Studies, Port St Lucie, FL
Department of Computer Science, University of Arizona, Tucson, AZ
BIO5 Interdisciplinary Research Institute, University of Arizona, Tucson, AZ
Translational Genomics Research Institute, Phoenix, AZ
Department of Pharmacology and Toxicology, Arizona Health Sciences Center, Tucson, AZ
Departments of Neurology and Cellular & Molecular Medicine, Arizona Health Sciences Center, Tucson, AZ
Center for Insect Science, Arizona Research Laboratories, University of Arizona, Tucson, AZ
MetadataShow full item record
PublisherThe Company of Biologists
CitationKraft et al. (2013). A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions. Dis Model Mech 6(1):217-35
JournalDisease Models & Mechanisms
RightsArchived with thanks to Disease models & mechanisms
AbstractThe actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the 'filagree' phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the 'beads-on-a-string' defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.
DescriptionA first-of-its-kind, proof-of-concept drug screen with implications for two unmet medical needs.
SponsorsNIH/NINDS: NS055774; U. of Arizona Center for Insect Science; State of Florida and the Menopause & Women’s Health Research Center (Port St Lucie, FL); NIGMS (Minority Access to Research Careers): T34 GM08718
CollectionsUA Faculty Publications
- Phenotypes of Drosophila brain neurons in primary culture reveal a role for fascin in neurite shape and trajectory.
- Authors: Kraft R, Escobar MM, Narro ML, Kurtis JL, Efrat A, Barnard K, Restifo LL
- Issue date: 2006 Aug 23
- Improving fascin inhibitors to block tumor cell migration and metastasis.
- Authors: Han S, Huang J, Liu B, Xing B, Bordeleau F, Reinhart-King CA, Li W, Zhang JJ, Huang XY
- Issue date: 2016 Aug
- p53 controls colorectal cancer cell invasion by inhibiting the NF-κB-mediated activation of Fascin.
- Authors: Sui X, Zhu J, Tang H, Wang C, Zhou J, Han W, Wang X, Fang Y, Xu Y, Li D, Chen R, Ma J, Jing Z, Gu X, Pan H, He C
- Issue date: 2015 Sep 8
- Migrastatin analogues target fascin to block tumour metastasis.
- Authors: Chen L, Yang S, Jakoncic J, Zhang JJ, Huang XY
- Issue date: 2010 Apr 15
- The prometastatic ribosomal S6 kinase 2-cAMP response element-binding protein (RSK2-CREB) signaling pathway up-regulates the actin-binding protein fascin-1 to promote tumor metastasis.
- Authors: Li D, Jin L, Alesi GN, Kim YM, Fan J, Seo JH, Wang D, Tucker M, Gu TL, Lee BH, Taunton J, Magliocca KR, Chen ZG, Shin DM, Khuri FR, Kang S
- Issue date: 2013 Nov 8