A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Le, X; Pugach, EK; Hettmer, S; Storer, NY; Liu, J; Wills, AA; DiBiase, A; Chen, EY; Ignatius, MS; Poss, KD; Wagers, AJ; Langenau, DM; Zon, LI

Published Date

  • June 2013

Published In

Volume / Issue

  • 140 / 11

Start / End Page

  • 2354 - 2364

PubMed ID

  • 23615277

Pubmed Central ID

  • 23615277

Electronic International Standard Serial Number (EISSN)

  • 1477-9129

Digital Object Identifier (DOI)

  • 10.1242/dev.088427

Language

  • eng

Conference Location

  • England