The MYC Oncogene as a Cancer Drug Target

Abstract

The universal deregulation of c-myc gene expression in tumor cells suggests that this oncogene represents an attractive target for cancer therapeutic purposes. The same applies to the N-myc gene, which has a more restricted tissue specificity. Translocation (e.g., c-myc in Burkitt's lymphoma), or amplification (e.g., N-myc in neuroblastoma) of myc genes has been causally linked to tumor formation. Furthermore, the c-myc promoter integrates diverse mitogenic signalling cascades, which are constitutively activated in tumor cells, and translates them into expression of the c-MYC transcription factor, which promotes cell proliferation by regulating the expression of numerous target genes. Recent experimental data suggest, that even a brief inhibition of c-myc expression may be sufficient to permanently stop tumor growth and induce regression of tumors. Attempts to identify specific inhibitors of c-MYC/MAX dimerization have yielded promising results. In addition, downstream-target genes of c-MYC represent attractive targets for tumor therapy. Tumor cells expressing c-MYC at elevated levels are sensitized to treatment with DNA-damaging drugs. In mice and presumably also in human patients, the successful treatment of c-myc-induced tumors with conventional chemotherapy depends on the presence of functional p53. Therefore, restoration of this pathway, which is commonly lost in cancer cells, may enhance therapy of c-myc-induced tumors. These and other recent developments, which address the use of myc genes as therapeutic targets for cancer treatment, are discussed in this review.

Polyamines and cancer: old molecules, new understanding

“…In addition, expression of spermidine/spermine N 1 -acetyltransferase (SSAT) is negatively regulated by the KRAS oncogene, which is commonly mutated -and, as a result, aberrantly activated -in human colon cancer and other gastrointestinal of which is associated with the development of Burkitt's lymphoma and several epithelial cancers, in addition to colorectal cancer 28 . MYC encodes a transcription factor that is required for the proliferation of some normal cells, but when overexpressed leads to uncontrolled growth and cancer 29 Figure 1 | Polyamine metabolism in mammals. The metabolism of arginine, which is produced in the urea cycle, through the action of arginase, results in the production of ornithine (other details of the urea cycle are not shown).…”

“…Increased levels of polyamine have long been associated with proliferation, and recent experiments with genetically altered rodents have confirmed the important roles of these molecules in both normal and neoplastic growth 53 . basis for neoplasia in Burkitt's lymphoma 29 . Inappropriate expression of MYC in models of this disease results in inappropriate ODC expression and tumorigenic phenotypes, including increased proliferation and decreased apoptosis 30,31 .…”

eIF4E – from translation to transformation

“…Deletion mutations in the c-myc 5'UTR, which are present in several Burkitt lymphomas (resulting from translocation of the c-myc gene), result in enhanced translation of the c-Myc mRNA (Saito et al, 1983;Darveau et al, 1985;Parkin et al, 1988;Carter et al, 1999;Willis, 1999). cmyc is implicated in several biological processes such as cell growth, proliferation and apoptosis (reviewed in Gartel and Shchors, 2003;Hermeking, 2003;Levens, 2003;Pelengaris and Khan, 2003). c-Myc is expressed ubiquitously during embryogenesis and in post-developmental tissues with a high proliferative capacity.…”

Human SWI/SNF Drives Sequence-Directed Repositioning of Nucleosomes on C-myc Promoter DNA Minicircles

“…Human SWI/SNF activity is important for the transcriptional activation of many genes, including the proto-oncogene c-myc, which is transcriptionally upregulated in many forms of human cancer (8,9). Chromatin immunoprecipitation experiments in vivo have shown that hSWI/SNF is present on the active c-myc promoter in proliferating T cells, but not the inactive promoter in resting T cells (10).…”