title: A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development.
abstract: The zebrafish is a powerful genetic model that has only recently been used to dissect developmental pathways involved in oncogenesis. We hypothesized that operative pathways during embryogenesis would also be used for oncogenesis. In an effort to define RAS target genes during embryogenesis, gene expression was evaluated in Tg(hsp70-HRAS(G12V)) zebrafish embryos subjected to heat shock. dusp6 was activated by RAS, and this was used as the basis for a chemical genetic screen to identify small molecules that interfere with RAS signaling during embryogenesis. A KRAS(G12D)-induced zebrafish embryonal rhabdomyosarcoma was then used to assess the therapeutic effects of the small molecules. Two of these inhibitors, PD98059 and TPCK, had anti-tumor activity as single agents in both zebrafish embryonal rhabdomyosarcoma and a human cell line of rhabdomyosarcoma that harbored activated mutations in NRAS. PD98059 inhibited MEK1 whereas TPCK suppressed S6K1 activity; however, the combined treatment completely suppressed eIF4B phosphorylation and decreased translation initiation. Our work demonstrates that the activated pathways in RAS induction during embryogenesis are also important in oncogenesis and that inhibition of these pathways suppresses tumor growth.
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xiuning
authors.initials: X
authors.lastname: Le
authors.forename: Emily K
authors.initials: EK
authors.lastname: Pugach
authors.forename: Simone
authors.initials: S
authors.lastname: Hettmer
authors.forename: Narie Y
authors.initials: NY
authors.lastname: Storer
authors.forename: Jianing
authors.initials: J
authors.lastname: Liu
authors.forename: Airon A
authors.initials: AA
authors.lastname: Wills
authors.forename: Antony
authors.initials: A
authors.lastname: DiBiase
authors.forename: Eleanor Y
authors.initials: EY
authors.lastname: Chen
authors.forename: Myron S
authors.initials: MS
authors.lastname: Ignatius
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Poss
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.forename: David M
authors.initials: DM
authors.lastname: Langenau
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D019076:Transgenes; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D039642:Eukaryotic Initiation Factors; D005419:Flavonoids; D029961:Zebrafish Proteins; C031799:eIF-4B; D014108:Tosylphenylalanyl Chloromethyl Ketone; D019893:Ribosomal Protein S6 Kinases; D048369:MAP Kinase Kinase 1; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Embryogenesis; RAS; Rhabdomyosarcoma; Translational control; Zebrafish