In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 16, No. 11 ( 2020-11-17), p. e1009117-
Abstract:
Glioblastoma is the most common and aggressive type of cancer in the brain; its poor prognosis is often marked by reoccurrence due to resistance to the chemotherapeutic agent temozolomide, which is triggered by an increase in the expression of DNA repair enzymes such as MGMT. The poor prognosis and limited therapeutic options led to studies targeted at understanding specific vulnerabilities of glioblastoma cells. Metabolic adaptations leading to increased synthesis of nucleotides by de novo biosynthesis pathways are emerging as key alterations driving glioblastoma growth. In this study, we show that enzymes necessary for the de novo biosynthesis of pyrimidines, DHODH and UMPS, are elevated in high grade gliomas and in glioblastoma cell lines. We demonstrate that DHODH’s activity is necessary to maintain ribosomal DNA transcription (rDNA). Pharmacological inhibition of DHODH with the specific inhibitors brequinar or ML390 effectively depleted the pool of pyrimidines in glioblastoma cells grown in vitro and in vivo and impaired rDNA transcription, leading to nucleolar stress. Nucleolar stress was visualized by the aberrant redistribution of the transcription factor UBF and the nucleolar organizer nucleophosmin 1 (NPM1), as well as the stabilization of the transcription factor p53. Moreover, DHODH inhibition decreased the proliferation of glioblastoma cells, including temozolomide-resistant cells. Importantly, the addition of exogenous uridine, which reconstitutes the cellular pool of pyrimidine by the salvage pathway, to the culture media recovered the impaired rDNA transcription, nucleolar morphology, p53 levels, and proliferation of glioblastoma cells caused by the DHODH inhibitors. Our in vivo data indicate that while inhibition of DHODH caused a dramatic reduction in pyrimidines in tumor cells, it did not affect the overall pyrimidine levels in normal brain and liver tissues, suggesting that pyrimidine production by the salvage pathway may play an important role in maintaining these nucleotides in normal cells. Our study demonstrates that glioblastoma cells heavily rely on the de novo pyrimidine biosynthesis pathway to generate ribosomal RNA (rRNA) and thus, we identified an approach to inhibit ribosome production and consequently the proliferation of glioblastoma cells through the specific inhibition of the de novo pyrimidine biosynthesis pathway.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009117
DOI:
10.1371/journal.pgen.1009117.g001
DOI:
10.1371/journal.pgen.1009117.g002
DOI:
10.1371/journal.pgen.1009117.g003
DOI:
10.1371/journal.pgen.1009117.g004
DOI:
10.1371/journal.pgen.1009117.g005
DOI:
10.1371/journal.pgen.1009117.g006
DOI:
10.1371/journal.pgen.1009117.s001
DOI:
10.1371/journal.pgen.1009117.s002
DOI:
10.1371/journal.pgen.1009117.s003
DOI:
10.1371/journal.pgen.1009117.s004
DOI:
10.1371/journal.pgen.1009117.s005
DOI:
10.1371/journal.pgen.1009117.s006
DOI:
10.1371/journal.pgen.1009117.s007
DOI:
10.1371/journal.pgen.1009117.s008
DOI:
10.1371/journal.pgen.1009117.s009
DOI:
10.1371/journal.pgen.1009117.s010
DOI:
10.1371/journal.pgen.1009117.s011
DOI:
10.1371/journal.pgen.1009117.s012
DOI:
10.1371/journal.pgen.1009117.s013
DOI:
10.1371/journal.pgen.1009117.s014
DOI:
10.1371/journal.pgen.1009117.s015
DOI:
10.1371/journal.pgen.1009117.s016
DOI:
10.1371/journal.pgen.1009117.s017
DOI:
10.1371/journal.pgen.1009117.s018
DOI:
10.1371/journal.pgen.1009117.s019
DOI:
10.1371/journal.pgen.1009117.s020
DOI:
10.1371/journal.pgen.1009117.r001
DOI:
10.1371/journal.pgen.1009117.r002
DOI:
10.1371/journal.pgen.1009117.r003
DOI:
10.1371/journal.pgen.1009117.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2186725-2
Permalink