(ChemotherapyAdvisor) – Inhibiting A20 E3 ligase can overcome TNF-related apoptosis-inducing ligand (TRAIL) resistance in glioblastoma, according to a study published in Cancer Discovery OnlineFirst January 24, 2012.
A20 E3 ligase acts as an oncogene inhibiting TRAIL-induced apoptosis and its identification as a therapeutic target will have an impact on ongoing cancer therapies, noted Chunhai Hao, MD, PhD, Emory University, Atlanta, GA, and colleagues. Previously, “clinical trials have proven that the vast majority of human cancers are resistant to TRAIL apoptotic pathway-targeted therapies” as a result of caspase-8-mediated apoptosis, the investigators wrote.
The study, which used tumor-initiating cells isolated from glioblastomas surgically removed from patients, found A20 E3 ligase to be highly expressed and, with receptor interacting protein 1 (RIP1) and caspase-8, forms a signaling complex. When TRAIL interacts with this complex, the A20 E3 ligase triggers ubiquitination of RIP1, interfering with activation of caspase-8 and preventing caspase-8-initiated apoptosis.
This research elucidates a mechanism for how the ubiquitination process can be manipulated to overcome resistance to apoptosis-targeted cancer therapies. Glioblastoma is the most common cause of brain cancer which has no curative treatment, and is resistant to most available therapies.