Data from Inhibition of Phosphatidylinositol 3-Kinase Destabilizes Mycn Protein and Blocks Malignant Progression in Neuroblastoma

Abstract

<div>Abstract<p>Amplification of <i>MYCN</i> occurs commonly in neuroblastoma. We report that phosphatidylinositol 3-kinase (PI3K) inhibition in murine neuroblastoma (driven by a tyrosine hydroxylase-<i>MYCN</i> transgene) led to decreased tumor mass and decreased levels of Mycn protein without affecting levels of MYCN mRNA. Consistent with these observations, PI3K inhibition in <i>MYCN</i>-amplified human neuroblastoma cell lines resulted in decreased levels of Mycn protein without affecting levels of MYCN mRNA and caused decreased proliferation and increased apoptosis. To clarify the importance of Mycn as a target of broad-spectrum PI3K inhibitors, we transduced wild-type <i>N-myc</i> and <i>N-myc</i> mutants lacking glycogen synthase kinase 3β phosphorylation sites into human neuroblastoma cells with no endogenous expression of myc. In contrast to wild-type <i>N-myc</i>, the phosphorylation-defective mutant proteins were stabilized and were resistant to the antiproliferative effects of PI3K inhibition. Our results show the importance of Mycn as a therapeutic target in established tumors <i>in vivo</i>, offer a mechanistic rationale to test PI3K inhibitors in <i>MYCN</i>-amplified neuroblastoma, and represent a therapeutic approach applicable to a broad range of cancers in which transcription factors are stabilized through a PI3K-dependent mechanism. (Cancer Res 2006; 66(16): 8139-46)</p></div>