Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma.
Neuroblastoma is a pediatric malignancy that arises from the neural crest, and patients with high-risk neuroblastoma, which typically harbor amplifications of MYCN, have an extremely poor prognosis. The tyrosine hydroxylase (TH) promoter-driven TH-MYCN transgenic mouse model faithfully recapitulates many hallmarks of human MYCN-amplified neuroblastoma. A key downstream target of Myc oncoproteins in tumorigenesis is ornithine decarboxylase (Odc), the rate-limiting enzyme of polyamine biosynthesis. Indeed, sustained treatment with the Odc suicide inhibitor alpha-difluoromethylornithine (DFMO) or Odc heterozygosity markedly impairs lymphoma development in Emicro-Myc transgenic mice, and these effects are linked to the induction of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1), which is normally repressed by Myc. Here, we report that DFMO treatment, but not Odc heterozygosity, impairs MYCN-induced neuroblastoma and that, in this malignancy, transient DFMO treatment is sufficient to confer protection. The selective anticancer effects of DFMO on mouse and human MYCN-amplified neuroblastoma also rely on its ability to disable the proliferative response of Myc, yet in this tumor context, DFMO targets the expression of the p21(Cip1) Cdk inhibitor, which is also suppressed by Myc oncoproteins. These findings suggest that agents, such as DFMO, that target the polyamine pathway may show efficacy in high-risk, MYCN-amplified neuroblastoma.
Rounbehler
Robert J
RJ
Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA.
Li
Weimin
W
Hall
Mark A
MA
Yang
Chunying
C
Fallahi
Mohammad
M
Cleveland
John L
JL
D000818:Animals; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005784:Gene Amplification; D006801:Humans; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; C489427:MYC protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D065108:Ornithine Decarboxylase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D009955:Ornithine Decarboxylase; D000518:Eflornithine