Bortezomib downregulates MGMT expression in T98G glioblastoma cells.

Abstract

The efficacy of treatment for glioblastoma multiforme is currently limited by the development of resistance, particularly, but not exclusively, due to the expression of the DNA repair enzyme O6-methylguanine methyltransferase (MGMT) in a significant proportion of astrocytic tumors. MGMT is post-translationally regulated by the 26S proteasome, a multi-subunit organelle responsible for degradation of misfolded cellular proteins. The boronic acid dipeptide bortezomib is the first and only proteasome inhibitor in clinical use so far, and has been reported as a strategy to restrict growth and promote apoptosis of glioblastoma cells. In this study we investigated the effect of bortezomib on MGMT expression in T98G cells, looking for an effect on the nuclear factor kappa B (NFκB) pathway, which is a major player in MGMT regulation and is also under tight control by the ubiquitin-proteasome system. Administration of bortezomib led to a significant reduction of T98G cell viability and induction of DNA fragmentation. These effects coincided with reduced expression of MGMT transcript levels, and a decrease in cellular amount and IκBα-mediated, proteasomal activity-dependent nuclear translocation of NFκB. In addition, bortezomib-induced phosphorylation of the translation initiation factor 2alpha (eIF2α) was in parallel with translational repression of MGMT. Taken together, these results suggest a novel role for bortezomib as a potent MGMT inhibitor and support its ongoing testing as a chemosensitizer in glioblastoma.

• Authors: Panagiotis J Vlachostergios, Eleana Hatzidaki, Nikolaos E Stathakis, George K Koukoulis, Christos N Papandreou
• Journal: Cellular and molecular neurobiology (Cell Mol Neurobiol) Vol. 33 Issue 3 Pg. 313-8 (Apr 2013) ISSN: 1573-6830 [Electronic] United States
• PMID: 23334228 (Publication Type: Journal Article)

Chemical References

• Boronic Acids
• Eukaryotic Initiation Factor-2
• NF-kappa B
• Pyrazines
• Tumor Suppressor Proteins
• Bortezomib
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes

Topics

• Apoptosis (drug effects, genetics)
• Boronic Acids (pharmacology)
• Bortezomib
• Brain Neoplasms (enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• DNA Modification Methylases (genetics, metabolism)
• DNA Repair Enzymes (genetics, metabolism)
• Down-Regulation (drug effects, genetics)
• Eukaryotic Initiation Factor-2 (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioblastoma (enzymology, genetics, pathology)
• Humans
• NF-kappa B (metabolism)
• Pyrazines (pharmacology)
• Signal Transduction (drug effects, genetics)
• Tumor Suppressor Proteins (genetics, metabolism)