Abstract
BackgroundGlioblastoma (GBM) is the most malignant primary brain tumor in adults, with a median survival time of one and a half years. Traditional treatments, including radiation, chemotherapy, and surgery, are not curative, making it imperative to find more effective treatments for this lethal disease. γ-Glutamyl transferase (GGT) is a family of enzymes that was shown to control crucial redox-sensitive functions and to regulate the balance between proliferation and apoptosis. GGT7 is a novel GGT family member that is highly expressed in brain and was previously shown to have decreased expression in gliomas. Since other members of the GGT family were found to be altered in a variety of cancers, we hypothesized that GGT7 could regulate GBM growth and formation.MethodsTo determine if GGT7 is involved in GBM tumorigenesis, we modulated GGT7 expression in two GBM cell lines (U87-MG and U138) and monitored changes in tumorigenicity in vitro and in vivo.ResultsWe demonstrated for the first time that GBM patients with low GGT7 expression had a worse prognosis and that 87% (7/8) of primary GBM tissue samples showed a 2-fold decrease in GGT7 expression compared to normal brain samples. Exogenous expression of GGT7 resulted in a 2- to 3-fold reduction in proliferation and anchorage-independent growth under minimal growth conditions (1% serum). Decreasing GGT7 expression using either short interfering RNA or short hairpin RNA consistently increased proliferation 1.5- to 2-fold. In addition, intracranial injections of U87-MG cells with reduced GGT7 expression increased tumor growth in mice approximately 2-fold, and decreased mouse survival. To elucidate the mechanism by which GGT7 regulates GBM growth, we analyzed reactive oxygen species (ROS) levels in GBM cells with modulated GGT7 expression. We found that enhanced GGT7 expression reduced ROS levels by 11-33%.ConclusionOur study demonstrates that GGT7 is a novel player in GBM growth and that GGT7 can play a critical role in tumorigenesis by regulating anti-oxidative damage. Loss of GGT7 may increase the cellular ROS levels, inducing GBM occurrence and growth. Our findings suggest that GGT7 can be a promising biomarker and a potential therapeutic target for GBM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1232-y) contains supplementary material, which is available to authorized users.
Highlights
Glioblastoma (GBM) is the most malignant primary brain tumor in adults, with a median survival time of one and a half years
After sorting the GBM patients into high or low GGT7 expression, our findings suggest that GBM patients with high GGT7 expression had a better prognosis compared with their low-expressing counterparts (P = 0.02) (Figure 1A)
GBM primary samples have reduced expression of GGT7 Since GGT7 is the only γ-glutamyl transferase (GGT) family member highly expressed in the brain to any extent, we compared its expression between primary GBM tissue and normal brain [9]
Summary
Glioblastoma (GBM) is the most malignant primary brain tumor in adults, with a median survival time of one and a half years. GGT7 may have a novel function as a result of the high variation in its light chain, compared with GGT1 and GGT5, resulting in altered substrate binding This discrepancy was evident when only GGT7 was found to interact with proteins associated with lung cancer, indicating it could play a role in cancer progression [8]. GGT7 differs from the other GGT isoforms, since it is the only isoform to have ~20-fold higher mRNA expression in the brain compared with other normal tissues [9] and has decreased expression in gliomas compared with the normal brain [10] These previous findings suggest that GGT7 could play an important role in GBM growth
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