Abstract
In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer, glioblastoma (GBM). This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein, Nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in GBM reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of GBM cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for aberrant nucleolar function and increased anabolic processes in GBM, which constitutes a primary event in gliomagenesis.
Highlights
In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy
By revealing that upregulation of IMP dehydrogenase-2 (IMPDH2) in GBM cells drives de novo GTP biosynthesis, enhances rRNA and tRNA synthesis, and stimulates nucleolar hypertrophy, connects these two long observed features of cancer (Fig. 7f)
Our primary result establishing a mechanistic connection between GTP metabolism, IMPDH2, nucleolar hypertrophy and malignancy prompts a reappraisal of the published literature on IMPDH
Summary
Increased rRNA synthesis[47] and nucleolar hypertrophy[1,2] have both long been recognized as features of malignant transformation. By revealing that upregulation of IMPDH2 in GBM cells drives de novo GTP biosynthesis, enhances rRNA and tRNA synthesis, and stimulates nucleolar hypertrophy, connects these two long observed features of cancer (Fig. 7f). Less proliferative, or quiescent cells, such as primary glia, have a nucleolus and continuously produce ribosomes This observation has at least two major implications: 1) insight into how metabolically inactive cells maintain ribosome biogenesis, one of the most anabolic cellular processes, and 2) the therapeutic potential of IMPDH pathway to suppress ribosome biogenesis in tumor cells but not in normal tissue. Other questions include what is mechanism regulating GTP-dependent Pol I and Pol III transcription, whether nucleolar enlargement is a passive structural manifestation, whether the nucleolar changes have an active role in directly promoting tumor growth, and could existing or more selective IMPDH inhibitors benefit and prolong the GBM patients’ survival while minimizing their strong immunosuppressive effects and other toxicities32,53,54? Other questions include what is mechanism regulating GTP-dependent Pol I and Pol III transcription, whether nucleolar enlargement is a passive structural manifestation, whether the nucleolar changes have an active role in directly promoting tumor growth, and could existing or more selective IMPDH inhibitors benefit and prolong the GBM patients’ survival while minimizing their strong immunosuppressive effects and other toxicities32,53,54? Further studies understanding tumor-specific regulation of IMPDH2 coupled with improved design of currently available IMPDH inhibitors[32,55] may open new avenues developing effective therapy for GBM and other types of cancers
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