This N-Myc degradation by FNIII14 reduced the malignant properties, including the anchorage-independent proliferation and invasive migration, of neuroblastoma cells.
In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway.
These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.
The present study evaluated the effect of ethanolic extract of <i>Nardostachys jatamansi</i> roots (NJ<sub>et</sub>) on MYCN mediated regulation of expression of MDM2 and p53 proteins in neuroblastoma cell lines, IMR-32 and SK-N-MC.
The proposed prognostic cell risk score (pCRS) model we constructed can be an independent prognostic indicator for overall survival (OS) and event-free survival (EFS) (training: OS, HR 1.579, EFS, HR 1.563; validation: OS, HR 1.665, 3.848, EFS, HR 2.203, all <i>p</i>-values < 0.01) and only independent prognostic factor in <i>International Neuroblastoma Risk Group</i> high risk patients (HR 1.339, 3.631; <i>p</i>-value 1.76e-2, 3.71e-5), rather than MYCN amplification.
Recent studies have identified alterations of the anaplastic lymphoma kinase (ALK) gene in neuroblastoma; ALK F1174L (a phenylalanine-to-leucine substitution at codon 1174) represents one of the most frequent of these somatic mutations, and is associated with amplification of the MYCN gene, the most reliable marker for the poor survival.
IBL-302 was more effective than single PI3K inhibition in vitro, and IBL-302 treatment of neuroblastoma patient-derived xenograft (PDX) cells induced apoptosis, differentiated tumor cells, and decreased N-Myc protein levels.
Collectively, targeting a combination of MYCN-targeted genes that interrupts the interconnection of metabolic pathways may overcome drug toxicity and improve the efficacy of current therapeutic agents in MNA neuroblastoma.
SIGNIFICANCE: This study presents a novel approach to drugging an amplified oncogene by showing that targeting gene amplification of <i>MYCN</i> suppresses MYCN expression and neuroblastoma growth.
In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression.
The tumor-suppressive miR-186 that is downregulated in neuroblastoma and in TGFβ-treated NK cells represses oncogenic proteins in neuroblastoma (MYCN and AURKA) and components of the TGFβ pathway.
Inhibition of MYCN caused profound mitochondrial damage in MNA neuroblastoma cells through downregulation of the mitochondrial molecular chaperone TRAP1, which subsequently increased ROS.
Interestingly, the forced expression of NR4A3 induced only the GAP43 but not the other molecules involved in NB cell differentiation, such as MYCN, TRKA, and PHOX2B.
Comparison with MRI and pathology from patients with MYCN-amplified neuroblastoma confirmed the high degree to which the Th-MYCN model vascular phenotype recapitulated that of the clinical phenotype, thereby supporting further evaluation of IS- and SC-MRI in the clinic.
Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease.
Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression.
In conclusion, our study is the first report to show the application of MYCN RNA in situ hybridization in neuroblastoma and established that high expression of MYCN RNA could be a better biomarker than MYCN amplification for predicting poor prognosis of neuroblastoma patients.