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.
Highlights
Neuroblastoma, a childhood tumor of the peripheral sympathetic nervous system, originates from neural crest cells and usually manifests in the adrenal gland or in a paraspinal location in the abdomen or chest
We demonstrate a strong correlation between advanced stage disease, high MYCN expression levels, and elevated expression of genes involved in ribosome biogenesis in several large neuroblastoma patient cohorts
Given that the expression of genes involved in ribosome biogenesis strongly correlated with neuroblastoma high-risk disease and prognosis, we evaluated the effects of two compounds inhibiting RNA polymerase I in a panel of neuroblastoma cells (Supplementary Table 1)
Summary
Neuroblastoma, a childhood tumor of the peripheral sympathetic nervous system, originates from neural crest cells and usually manifests in the adrenal gland or in a paraspinal location in the abdomen or chest. A molecular hallmark of high-risk neuroblastoma is genetic amplification and high expression of the MYCN oncogene [2]. Single-copy high-risk neuroblastomas frequently show high expression of the MYCN homolog cMYC [3]. MycN has been shown to positively regulate the expression of a large set of genes involved in ribosomal biogenesis [6], and c-Myc is well-established as a driver of this process [7]. In line with these observations, tumor cells from MYC-driven neuroblastomas frequently display nucleolar hypertrophy [8, 9]. Inhibition of RNA pol I activity has been shown to induce apoptosis, nucleolar surveillance signaling, p53 pathway activation, senescence, and pro-death autophagy [11,12,13,14]
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