دورية أكاديمية
أعرض في EDS

A zebrafish embryo screen utilizing gastrulation identifies the HTR2C inhibitor pizotifen as a suppressor of EMT-mediated metastasis.

التفاصيل البيبلوغرافية
العنوان: A zebrafish embryo screen utilizing gastrulation identifies the HTR2C inhibitor pizotifen as a suppressor of EMT-mediated metastasis.
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
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.70151