Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation

Abstract

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.

Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions

“…It was shown that in some cases the increased ODC activity is a direct result of elevated ODC expression (Nilsson et al, 2005). On the other hand, based on our present results and on a recent observation demonstrating increased levels of AzI mRNA in gastric tumors (Jung et al, 2000), we propose here that augmented levels of ODC can be caused by its stabilization due to elevated AzI expression that neutralizes Az functions (Figure 7).…”

“…In some cases, ODC overexpression is sufficient to induce cellular transformation (Auvinen et al, 1992;Moshier et al, 1993;Shantz and Pegg, 1994;Clifford et al, 1995), and spontaneous skin tumors in nude mice (Megosh et al, 1995). Recently, ODC was found to be an important downstream mediator of Myc-and APCdependent transformation pathways (Gerner and Meyskens, 2004;Nilsson et al, 2005).…”

Deregulated expression of a novel component of TFTC/STAGA histone acetyltransferase complexes, rat SGF29, in hepatocellular carcinoma: possible implication for the oncogenic potential of c-Myc

“…Two downstream genes, MTA1 and ODC, are well documented to cause the c-Myc-mediated malignant phenotypes, including anchorage-independent growth (Nilsson et al, 2005;Zhang et al, 2005). Downregulation of rSGF29 in K2 cells, in which both rSGF29 and c-myc gene expressions were deregulated, caused the reduction of their colony-forming ability in soft agar, showing that deregulated expression of rSGF29 is implicated in malignant transformation.…”

Lessons from Functional Analysis of Genome-Wide Association Studies

“…36). Genetic evidence in mouse models shows that targeting proteins that act downstream of Myc, for example via ribosomal haploinsufficiency or by targeting ornithine decarboxylase, is a successful strategy without significant adverse effects (37,38). In addition, targeting a specific function of MYC itself, for instance, by expressing the dominant negative form of Myc (Omomyc) also results in an efficient and safe treatment in transgenic mouse cancer models (39).…”