BBB seminar: Marie Arsenian Henriksson
The Myc oncogene as a target for therapy
Marie Arsenian Henriksson
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
The Myc oncogene is deregulated in a wide variety of human tumors and is therefore an attractive target for novel cancer therapies. Using a cellular screening approach we have identified two low molecular weight compounds, Myc pathway response agents (MYRAs), that predominantly suppress proliferation in Myc-overexpressing cells compared to cells with wild type Myc levels. Both MYRA-A and MYRA-B induce apoptosis in a Myc dependent manner and inhibit Myc-driven transformation. However, their mechanism of action is different; MYRA-A inhibits Myc transactivation and interferes with the DNA-binding activity of Myc family proteins. In contrast, MYRA-B induces Myc-dependent apoptosis without affecting Myc transcativation and Myc/Max DNA binding. In the screen we further identified a third compound that resulted in decreased Myc protein levels and in inhibitory effects also on other transcription factors than Myc. Taken together, our findings suggest that these three small molecules can elicit a similar biological response, induction of apoptosis, by interfering with the Myc pathway at different levels. We are continuing to characterize these molecules in parallel with performing novel screenings. Data from these studies will be presented.
In summary, our data suggest that cellular screening assays can be a powerful strategy for the identification of candidate substances that modulate the Myc pathway. These compounds can be useful tools for studying Myc function and may also be of therapeutic potential as leads for medical chemistry and drug development.
Mo, H., and Henriksson, M. Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation. PNAS USA 103, 6344-6349, 2006.
Mo, H., Vita, M., Crespin, M., and Henriksson, M. Myc overexpression enhances apoptosis induced by small molecules. Cell Cycle 5, 2191-2194, 2006.
Vita, M., and Henriksson, M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 16, 318-330, 2006.
Host: Donald Gullberg, Department of Biomedicine