Inhibitors of ribosome biogenesis repress the growth of MYCN-amplified neuroblastoma.
Øyvind H HaldLotte OlsenGabriel Gallo-OllerLotta Helena Maria ElfmanCecilie LøkkePer KognerBaldur SveinbjörnssonTrond FlægstadJohn Inge JohnsenChrister EinvikPublished in: Oncogene (2018)
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.
Keyphrases
- cell cycle arrest
- poor prognosis
- cell death
- small molecule
- dna damage
- transcription factor
- binding protein
- oxidative stress
- end stage renal disease
- chronic kidney disease
- type diabetes
- genome wide
- long non coding rna
- prognostic factors
- induced apoptosis
- protein protein
- dna methylation
- endoplasmic reticulum stress
- metabolic syndrome
- dna repair
- signaling pathway
- endothelial cells
- high glucose
- early life
- wild type