Manipulating the Ubiquitination Process May Overcome Glioblastoma Resistance
By LabMedica International staff writers Posted on 09 Feb 2012 |
A complex molecular pathway protects glioblastoma, an aggressive and lethal brain cancer, from treatment based on drugs that target the TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL) apoptotic pathway.
The TRAIL apoptotic pathway has emerged as a therapeutic target for the treatment of cancer. However, clinical trials have proven that the vast majority of human cancers are resistant to this approach. In a study seeking ways to overcome this resistance, investigators at Emory University (Philadelphia, PA, USA) worked with tumor-initiating cells isolated from glioblastomas surgically removed from patients.
They reported in the January 24, 2012 online edition of the journal Cancer Discovery that A20 E3 (tumor necrosis factor, alpha-induced protein 3 or TNFAIP3) ligase was highly expressed in these cells along with receptor interacting protein 1 (RIP1), and the apoptotic protein caspase-8. Together, these proteins formed a potent signaling complex.
When TRAIL interacted with this complex, the A20 E3 ligase triggered ubiquitination and destruction of RIP1, which interfered with activation of caspase-8 and prevented caspase-8-initiated apoptosis.
These results identify A20 E3 ligase as a therapeutic target whose inhibition can overcome TRAIL resistance in glioblastoma. “Scientists in this field have been hoping to treat this cancer with this new type of apoptosis pathway-targeted therapeutic drug, and this new information may provide a path forward,” said senior author Dr. Chunhai Hao, professor of neuropathology at Emory University.
“Previous research in this area has been unable to overcome the obstacle created by resistance,” said Dr. Hao. “This research shows one of the mechanisms for how we can manipulate the ubiquitination process to overcome the resistance to the apoptosis-targeted cancer therapies. Understanding the mechanisms of resistance is vital to developing therapies going forward.”
Related Links:
Emory University
The TRAIL apoptotic pathway has emerged as a therapeutic target for the treatment of cancer. However, clinical trials have proven that the vast majority of human cancers are resistant to this approach. In a study seeking ways to overcome this resistance, investigators at Emory University (Philadelphia, PA, USA) worked with tumor-initiating cells isolated from glioblastomas surgically removed from patients.
They reported in the January 24, 2012 online edition of the journal Cancer Discovery that A20 E3 (tumor necrosis factor, alpha-induced protein 3 or TNFAIP3) ligase was highly expressed in these cells along with receptor interacting protein 1 (RIP1), and the apoptotic protein caspase-8. Together, these proteins formed a potent signaling complex.
When TRAIL interacted with this complex, the A20 E3 ligase triggered ubiquitination and destruction of RIP1, which interfered with activation of caspase-8 and prevented caspase-8-initiated apoptosis.
These results identify A20 E3 ligase as a therapeutic target whose inhibition can overcome TRAIL resistance in glioblastoma. “Scientists in this field have been hoping to treat this cancer with this new type of apoptosis pathway-targeted therapeutic drug, and this new information may provide a path forward,” said senior author Dr. Chunhai Hao, professor of neuropathology at Emory University.
“Previous research in this area has been unable to overcome the obstacle created by resistance,” said Dr. Hao. “This research shows one of the mechanisms for how we can manipulate the ubiquitination process to overcome the resistance to the apoptosis-targeted cancer therapies. Understanding the mechanisms of resistance is vital to developing therapies going forward.”
Related Links:
Emory University
Latest BioResearch News
- Genome Analysis Predicts Likelihood of Neurodisability in Oxygen-Deprived Newborns
- Gene Panel Predicts Disease Progession for Patients with B-cell Lymphoma
- New Method Simplifies Preparation of Tumor Genomic DNA Libraries
- New Tool Developed for Diagnosis of Chronic HBV Infection
- Panel of Genetic Loci Accurately Predicts Risk of Developing Gout
- Disrupted TGFB Signaling Linked to Increased Cancer-Related Bacteria
- Gene Fusion Protein Proposed as Prostate Cancer Biomarker
- NIV Test to Diagnose and Monitor Vascular Complications in Diabetes
- Semen Exosome MicroRNA Proves Biomarker for Prostate Cancer
- Genetic Loci Link Plasma Lipid Levels to CVD Risk
- Newly Identified Gene Network Aids in Early Diagnosis of Autism Spectrum Disorder
- Link Confirmed between Living in Poverty and Developing Diseases
- Genomic Study Identifies Kidney Disease Loci in Type I Diabetes Patients
- Liquid Biopsy More Effective for Analyzing Tumor Drug Resistance Mutations
- New Liquid Biopsy Assay Reveals Host-Pathogen Interactions
- Method Developed for Enriching Trophoblast Population in Samples