Targeting Ornithine Decarboxylase Impairs Development of MYCN-Amplified Neuroblastoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-01, Vol.69 (2), p.547-553
• Main Authors: ROUNBEHLER, Robert J, WEIMIN LI, HALL, Mark A, CHUNYING YANG, FALLAHI, Mohammad, CLEVELAND, John L
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Eflornithine - pharmacology; Enzyme Inhibitors - pharmacology; Gene Amplification; Humans; Medical sciences; Mice; N-Myc Proto-Oncogene Protein; Neuroblastoma - drug therapy; Neuroblastoma - enzymology; Neuroblastoma - genetics; Neurology; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Oncogene Proteins - biosynthesis; Oncogene Proteins - genetics; Ornithine Decarboxylase - biosynthesis; Ornithine Decarboxylase - metabolism; Ornithine Decarboxylase Inhibitors; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tumors; Tumors of the nervous system. Phacomatoses
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-08-2968

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.