دورية أكاديمية
A zebrafish embryo screen utilizing gastrulation identifies the HTR2C inhibitor pizotifen as a suppressor of EMT-mediated metastasis.
العنوان: | A zebrafish embryo screen utilizing gastrulation identifies the HTR2C inhibitor pizotifen as a suppressor of EMT-mediated metastasis. |
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المؤلفون: | Nakayama J; Department of Biological Science, National University of Singapore, Singapore, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan.; Shonai Regional Industry Promotion Center, Tsuruoka, Japan., Tan L; Department of Biological Science, National University of Singapore, Singapore, Singapore., Li Y; Department of Biological Science, National University of Singapore, Singapore, Singapore., Goh BC; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Wang S; Department of Biological Science, National University of Singapore, Singapore, Singapore.; Institute of Bioengineering and Nanotechnology, Singapore, Singapore., Makinoshima H; Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan.; Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan., Gong Z; Department of Biological Science, National University of Singapore, Singapore, Singapore. |
المصدر: | ELife [Elife] 2021 Dec 17; Vol. 10. Date of Electronic Publication: 2021 Dec 17. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012- |
مواضيع طبية MeSH: | Epithelial-Mesenchymal Transition*, Cell Movement/*drug effects , Embryo, Nonmammalian/*drug effects , Gastrulation/*drug effects , High-Throughput Screening Assays/*methods , Pizotyline/*pharmacology , Receptor, Serotonin, 5-HT2C/*genetics , Serotonin 5-HT2 Receptor Antagonists/*pharmacology, Animals ; Drug Discovery ; Female ; Humans ; Mice, Inbred BALB C ; Neoplasm Metastasis/drug therapy ; Neoplasm Metastasis/prevention & control ; Signal Transduction/drug effects ; Small Molecule Libraries/pharmacology ; Transplantation, Heterologous ; Zebrafish ; Zebrafish Proteins/genetics ; Mice |
مستخلص: | Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in 5 hr. The screen tested 1280 FDA-approved drugs and identified pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacological and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt signaling. In contrast, HTR2C induced epithelial-to-mesenchymal transition through activation of Wnt signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs. Competing Interests: JN, LT, YL, BG, SW, HM, ZG No competing interests declared (© 2021, Nakayama et al.) |
التعليقات: | Comment in: Elife. 2022 Feb 08;11:e76632. doi: 10.7554/eLife.76632. (PMID: 35133278) Erratum in: Elife. 2024 Jul 31;13:e101706. doi: 10.7554/eLife.101706. (PMID: 39082603) |
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فهرسة مساهمة: | Keywords: EMT; developmental biology; gastrulation; metastasis; mice; phenotyping screening; serotonin; zebrafish |
المشرفين على المادة: | 0 (Receptor, Serotonin, 5-HT2C) 0 (Serotonin 5-HT2 Receptor Antagonists) 0 (Small Molecule Libraries) 0 (Zebrafish Proteins) 0BY8440V3N (Pizotyline) |
تواريخ الأحداث: | Date Created: 20211217 Date Completed: 20220222 Latest Revision: 20240802 |
رمز التحديث: | 20240802 |
مُعرف محوري في PubMed: | PMC8824480 |
DOI: | 10.7554/eLife.70151 |
PMID: | 34919051 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2050-084X |
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DOI: | 10.7554/eLife.70151 |