Stmc-22. a biosynthetic metabolic pathway in glioblastoma controls growth via reactive species balance

In glioblastoma (GBM; grade IV astrocytoma), subpopulations of highly tumorigenic cells called brain tumor initiating cells (BTICs) have been characterized by their unique capacity to promote tumor growth and therapeutic resistance. BTIC maintenance is increased via nitric oxide produced by nitric oxide synthases (NOS) in BTICs and the tumor vasculature. NOS require the co-factor tetrahydrobiopterin (BH4) for NO generation and will make superoxide if BH4 is deficient. As the first and rate-limiting enzyme of the de novo pathway synthesizing BH4 is GTP cyclohydrolase 1 (GCH1), GCH1 activity can control reactive nitrogen and oxygen species levels. We determined that GCH1 RNA and protein expression are increased in BTICs in comparison to non-BTICs. Overexpression of GCH1 in GBM cells increased cell growth in vitro and decreased survival in an intracranial GBM mouse model. In contrast, GCH1 knockdown with short hairpin RNA in GBM cells led to growth inhibition in vitro and also increased survival in animal models. When we inhibited GCH1 in BTICs with the small molecule inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP), neurosphere formation was decreased as was subcutaneous tumor growth. Effects of genetic or pharmacologic inhibition of GCH1 correlated with decreased NO and increased ROS production. In silico analyses demonstrate that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence and worse survival. Together, our data suggest that upregulatio...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research