BioProject

Ribonucleotides serve important cellular functions as energy carriers, signaling molecules and building blocks of RNA. More...

Ribonucleotides serve important cellular functions as energy carriers, signaling molecules and building blocks of RNA. In eukaryotes, rRNA and tRNA synthesis in the nucleolus accounts together for over 90% of all RNA molecules. In many cancers, high proliferation rates correlated with elevation of rRNA and tRNA levels4 and nucleolar hypertrophy. However, the metabolic changes that lead to the increased nucleolar transcription and in turn foster tumorigenesis are incompletely understood. Here we show that in the highly lethal brain cancer glioblastoma (GBM), inosine monophosphate dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed. This leads to increased rRNA and tRNA synthesis and stabilization of the oncogenic GTP-binding protein nucleostemin, and enlarged and malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 reverses these malignant effects and inhibits GBM cell proliferation, whereas untransformed glia cells are unaffected. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of GBM cells even in the absence of functional p53. Our results have uncovered upregulation of IMPDH2 as a prerequisite for aberrant nucleolar function and translational capacity in GBM. This GTP metabolic reprogramming constitutes a primary event in gliomagenesis and has implications for GBM treatment and possible malignant transformation in other cancers. Overall design: U87MG cells were treated with 10 μM (mycophenolic acid) MPA and/or 100 μM guanosine for 24 hr. DMSO treatment was used as a control. Total RNA was prepared at 24 hr after treatment. Less...