Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.
2005 (English)In: Cancer Cell, ISSN 1535-6108, Vol. 7, no 5, 433-44 p.Article in journal (Refereed) Published
Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.
Place, publisher, year, edition, pages
2005. Vol. 7, no 5, 433-44 p.
Animals, Apoptosis/drug effects, B-Lymphocytes/chemistry/drug effects/metabolism, Cell Cycle Proteins/genetics/metabolism, Cell Proliferation/drug effects, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Eflornithine/pharmacology, Gene Expression/drug effects, Gene Expression Regulation; Neoplastic/drug effects, Heterozygote, Lymphoma/drug therapy/genetics/*metabolism, Mice, Mice; Inbred C57BL, Mice; Knockout, Mice; Mutant Strains, Mice; Transgenic, Organ Size/drug effects, Ornithine Decarboxylase/antagonists & inhibitors/genetics/*metabolism, Polyamines/metabolism, Proto-Oncogene Proteins c-myc/genetics/*metabolism, Spleen/pathology, Survival Rate, Tumor Suppressor Protein p14ARF/genetics/metabolism, Tumor Suppressor Proteins/genetics/metabolism
IdentifiersURN: urn:nbn:se:umu:diva-16704PubMedID: 15894264OAI: oai:DiVA.org:umu-16704DiVA: diva2:156377