Research
Cancer Target Discoveries and Therapeutics
Myc-Mediated Pathways in Cancer and Development
Myc oncoproteins function as master regulators of transcription and regulate up to 10%–15% of the genome. Three Myc oncogenes (c-Myc, N-Myc, L-Myc) are activated in about 70% of human cancers. Their activation can occur directly via gene amplification, chromosomal translocations, or somatic missense mutations or indirectly via alterations in signal transduction pathways or the loss of tumor suppressors that normally regulate and/or harness Myc expression. The pervasive selection for Myc activation in cancer in part reflects the essential roles of Myc as a regulator of cell growth and division, but overexpression of Myc also triggers accelerated rates of cell proliferation, tumor angiogenesis, and metastasis. Further, Myc regulates stem cell fate and supercompetition, a scenario in which cells that overexpress Myc kill their neighboring, normal cells.
We have used mouse models to dissect the contribution of key targets downstream of Myc that control tumorigenesis. In normal cells, Myc triggers apoptosis through the Arf-p53 tumor suppressor pathway that is inactivated in most malignant tumors and by selectively affecting the expression of members of the Bcl-2 family of proteins that directly control the intrinsic apoptotic pathway. We have shown that these pathways hold Myc-induced tumorigenesis in check and that mutations in these apoptotic regulators are a hallmark of most malignant tumors.
Although apoptotic regulators clearly serve as guardians against Myc-induced cancer, we have found that the ability of Myc to provoke accelerated cell growth is also critical for tumorigenesis. First, Myc coordinately regulates the expression of cytokines that direct cell growth and tumor angiogenesis. Second, Myc suppresses expression of the universal cyclin-dependent kinase (Cdk) inhibitor p27Kip1 that normally inhibits the activity of cyclin E–Cdk2 and cyclin A–Cdk2 complexes that are necessary for entry and progression through the DNA synthesis (S) phase of the cell cycle. Notably, we found that Myc suppresses p27Kip1 protein levels by inducing transcription of the Cks1 component of the SCFSkp2 E3 ubiquitin ligase complex that targets p27Kip1 for destruction by the 26S proteasome. Accordingly, loss of Cks1 disables the ability of Myc to suppress p27Kip1 and markedly impairs Myc-induced proliferation and tumorigenesis, whereas loss of p27Kip1 accelerates Myc- induced tumorigenesis. Remarkably, Cks1 overexpression is a hallmark of all lymphomas with Myc involvement, suggesting this pathway is a general route by which Myc coordinates cell growth and division and that the pathway can be targeted by directed therapeutic agents.
Because Myc regulates such a large number of genes and is essential for cell growth and division, the adverse effects of agents that directly target the transcription functions of Myc might be greater than the agents’ beneficial effects. We therefore have focused our efforts on key transcription targets of Myc that might be suitable therapeutic targets. We found that inhibiting ornithine decarboxylase, a direct transcription target of Myc and the rate-limiting enzyme of polyamine biosynthesis, impairs Myc-induced proliferation and tumorigenesis. These results were underscored by our findings that heterozygosity in the gene that encodes ornithine decarboxylase, a condition that only reduces the enzyme activity of ornithine decarboxylase and the generation of its product by half, triples the life span of tumor-prone mice. Thus, agents that target the polyamine pathway have promise in both the prevention and the treatment of cancer. Currently, we are defining the mechanism by which targeting ornithine decarboxylase disables the proliferative response of Myc. Our results indicate, quite remarkably, that targeting ornithine decarboxylase disables the ability of Myc to suppress p27Kip1 by short- circuiting of the Myc-to-Cks1 pathway.
Finally, we recently discovered that additional Myc transcription targets that can be exploited in cancer therapy include components of the autophagy pathway, an ancient survival pathway that directs the digestion of bulk cytoplasmic material and organelles when cells are faced with nutrient- or oxygen-deprived conditions, a scenario manifests in the tumor microenvironment. We have shown that agents that disable autophagy have tremendous potential in cancer prevention and treatment. Currently, we are defining the mechanisms by which Myc regulates the expression of genes that control the autophagy pathway and their potential as targets for agents to prevent and treat cancer.
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