2. Academic Validation
  3. Inhibitors of ribosome biogenesis repress the growth of MYCN-amplified neuroblastoma

Inhibitors of ribosome biogenesis repress the growth of MYCN-amplified neuroblastoma

  • Oncogene. 2019 Apr;38(15):2800-2813. doi: 10.1038/s41388-018-0611-7.
Øyvind H Hald 1,  Lotte Olsen 2,  Gabriel Gallo-Oller 3,  Lotta Helena Maria Elfman 3,  Cecilie Løkke 2,  Per Kogner 3,  Baldur Sveinbjörnsson 3 4,  Trond Flægstad 1 2,  John Inge Johnsen 3,  Christer Einvik 5 6
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Child and Adolescent Health, UNN - University Hospital of North-Norway, NO-9038, Tromsø, Norway.
  • 2 Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037, Tromsø, Norway.
  • 3 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, 171 76, Stockholm, Sweden.
  • 4 Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037, Tromsø, Norway.
  • 5 Department of Pediatrics, Division of Child and Adolescent Health, UNN - University Hospital of North-Norway, NO-9038, Tromsø, Norway. christer.einvik@uit.no.
  • 6 Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037, Tromsø, Norway. christer.einvik@uit.no.
PMID: 30542116 DOI: 10.1038/s41388-018-0611-7
Abstract

Abnormal increases in nucleolar size and number caused by dysregulation of ribosome biogenesis has emerged as a hallmark in the majority of spontaneous cancers. The observed ribosome hyperactivity can be directly induced by the MYC transcription factors controlling the expression of RNA and protein components of the ribosome. Neuroblastoma, a highly malignant childhood tumor of the sympathetic nervous system, is frequently characterized by MYCN gene amplification and high expression of MYCN and c-Myc signature genes. Here, we show a strong correlation between high-risk disease, MYCN expression, poor survival, and ribosome biogenesis in neuroblastoma patients. Treatment of neuroblastoma cells with quarfloxin or CX-5461, two small molecule inhibitors of RNA polymerase I, suppressed MycN expression, induced DNA damage, and activated p53 followed by cell cycle arrest or Apoptosis. CX-5461 repressed the growth of established MYCN-amplified neuroblastoma xenograft tumors in nude mice. These findings suggest that inhibition of ribosome biogenesis represent new therapeutic opportunities for children with high-risk neuroblastomas expressing high levels of Myc.

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