Virginia Commonwealth University Massey Cancer Center researcher Steven Grant, M.D., and a team of VCU Massey researchers have uncovered the mechanism by which leukemia cells trigger a protective response when exposed to a class of cancer-killing agents known as histone deacetylase inhibitors (HDACIs). The findings, published in the Journal of Biological Chemistry, could lead to more effective treatments in patients with leukemia and other cancers of the blood.
The discovery centers on modification of a protein known as NEMO. Researchers have known for some time that HDACIs trigger a protective response in leukemia cells by activating a survival signaling pathway known as NF-κB, which limits the ability of HDACIs to initiate a cancer cell suicide program known as apoptosis. However, it was previously thought this process occurred through activation of receptors residing on the cancer cell surface. What VCU Massey researchers discovered was that HDACIs initially induce DNA damage within the cell nucleus, leading to modification of the NEMO protein, which then triggers the cytoprotective NF-κB pathway. By disrupting modifications of the NEMO protein, NF-κB activation can be prevented and, as a consequence, the cancer-killing capacity of HDACIs increases dramatically.
HDACIs represent an approved form of treatment for certain forms of lymphoma, and VCU Massey Cancer Center has been working for more than seven years to develop strategies designed to improve their effectiveness in leukemia and other blood cancers. Grant’s team is now focusing on ways to capitalize on this discovery by designing strategies that interrupt NEMO modifications through the use of pharmacologic agents and other means.
Grant’s research team included Roberto Rosato, Ph.D., of the Department of Internal Medicine at VCU; Paul Dent, Ph.D., Universal Professor for Signal Transduction at VCU Massey Cancer Center and vice chair of research in the Department of Neurosurgery at VCU; and Paul Fisher, M.Ph., Ph.D., Thelma Newmeyer Corman Endowed Chair in Cancer Research at VCU Massey Cancer Center, chair of VCU’s Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine.