Blockade of Crk eliminates Yki/YAP-activated tumors via JNK-mediated apoptosis in Drosophila

Commun Biol. 2024 Sep 28;7(1):1196. doi: 10.1038/s42003-024-06897-w.

Abstract

Selective elimination of cancer cells without causing deleterious effects on normal cells is an ideal anti-cancer strategy. Here, using Drosophila cancer model, we performed an in vivo RNAi screen for anti-cancer targets that selectively eliminate tumors without affecting normal tissue growth. In Drosophila imaginal epithelium, clones of cells expressing oncogenic Ras with simultaneous mutations in the cell polarity gene scribble (RasV12/scrib-/-) develop into malignant tumors. We found that knockdown of Crk, the Drosophila ortholog of human CRK (CT10 regulatory kinase) and CRKL (Crk-like) adapter proteins, significantly suppresses growth of RasV12/scrib-/- tumors by inducing c-Jun N-terminal kinase (JNK)-mediated apoptosis, while it does not affect growth of normal epithelium. Mechanistically, Crk inhibition blocks Yorkie (Yki)/YAP activity by impairing F-actin accumulation, an upstream event of Yki/YAP activation in tumors. Inhibition of Yki/YAP in tumors causes intracellular JNK signaling to be used for apoptosis induction. Given that molecules and signaling pathways identified in Drosophila are highly conserved and activated in human cancers, our findings would provide a novel, to the best of our knowledge, anti-cancer strategy against YAP-activated cancers.

MeSH terms

  • Animals
  • Apoptosis*
  • Drosophila / genetics
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster / genetics
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-crk / genetics
  • Proto-Oncogene Proteins c-crk / metabolism
  • Trans-Activators* / genetics
  • Trans-Activators* / metabolism
  • YAP-Signaling Proteins* / genetics
  • YAP-Signaling Proteins* / metabolism

Substances

  • Drosophila Proteins
  • YAP-Signaling Proteins
  • Yki protein, Drosophila
  • Trans-Activators
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-crk
  • hpo protein, Drosophila
  • JNK Mitogen-Activated Protein Kinases
  • Protein Serine-Threonine Kinases
  • Intracellular Signaling Peptides and Proteins