Data from Combinatorial Regulation of Neuroblastoma Tumor Progression by N-Myc and Hypoxia Inducible Factor HIF-1α

Abstract

<div>Abstract<p>In human neuroblastoma, amplification of the <i>MYCN</i> gene predicts poor prognosis and resistance to therapy. Because hypoxia contributes to aggressive tumor phenotypes, predominantly via two structurally related hypoxia inducible factors, HIF-1α and HIF-2α, we examined hypoxia responses in <i>MYCN</i>-amplified neuroblastoma cells. We demonstrate here that HIF-1α, but not HIF-2α, is preferentially expressed in both <i>MYCN</i>-amplified neuroblastoma cells and primary tumors in comparison to samples without <i>MYCN</i> amplification. Our results showed that interplay between N-Myc and HIF-1α plays critical roles in neuroblastoma. For example, high levels of N-Myc override HIF-1α inhibition of cell cycle progression, enabling continued proliferation under hypoxia. Furthermore, both HIF-1α and N-Myc are essential for the Warburg effect (aerobic glycolysis) in neuroblastomas by activating the transcription of multiple glycolytic genes. Of note, expressions of Phosphoglycerate Kinase 1 (<i>PGK1</i>), Hexokinase 2 (<i>HK2</i>), and Lactate Dehydrogenase A (<i>LDHA</i>) were each significantly higher in <i>MYCN</i>-amplified neuroblastomas than in tumors without <i>MYCN</i> amplification. Interestingly, <i>MYCN</i>-amplified neuroblastoma cells are “addicted” to LDHA enzymatic activity, as its depletion completely inhibits tumorigenesis <i>in vivo</i>. Thus, our results provide mechanistic insights explaining how <i>MYCN</i>-amplified neuroblastoma cells contend with hypoxic stress and paradoxically how hypoxia contributes to neuroblastoma aggressiveness through combinatorial effects of N-Myc and HIF-1α. These results also suggest that LDHA represents a novel, pharmacologically tractable target for neuroblastoma therapeutics. <i>Cancer Res; 70(24); 10351–61. ©2010 AACR.</i></p></div>