Journal article
Induction of the unfolded protein response drives enhanced metabolism and chemoresistance in glioma cells
PloS one, Vol.8(8), pp.e73267-e73267
2013
DOI: 10.1371/journal.pone.0073267
PMCID: PMC3748289
PMID: 24039668
Abstract
The unfolded protein response (UPR) is an endoplasmic reticulum (ER)-based cytoprotective mechanism acting to prevent pathologies accompanying protein aggregation. It is frequently active in tumors, but relatively unstudied in gliomas. We hypothesized that UPR stress effects on glioma cells might protect tumors from additional exogenous stress (ie, chemotherapeutics), postulating that protection was concurrent with altered tumor cell metabolism. Using human brain tumor cell lines, xenograft tumors, human samples and gene expression databases, we determined molecular features of glioma cell UPR induction/activation, and here report a detailed analysis of UPR transcriptional/translational/metabolic responses. Immunohistochemistry, Western and Northern blots identified elevated levels of UPR transcription factors and downstream ER chaperone targets in gliomas. Microarray profiling revealed distinct regulation of stress responses between xenograft tumors and parent cell lines, with gene ontology and network analyses linking gene expression to cell survival and metabolic processes. Human glioma samples were examined for levels of the ER chaperone GRP94 by immunohistochemistry and for other UPR components by Western blotting. Gene and protein expression data from patient gliomas correlated poor patient prognoses with increased expression of ER chaperones, UPR target genes, and metabolic enzymes (glycolysis and lipogenesis). NMR-based metabolomic studies revealed increased metabolic outputs in glucose uptake with elevated glycolytic activity as well as increased phospholipid turnover. Elevated levels of amino acids, antioxidants, and cholesterol were also evident upon UPR stress; in particular, recurrent tumors had overall higher lipid outputs and elevated specific UPR arms. Clonogenicity studies following temozolomide treatment of stressed or unstressed cells demonstrated UPR-induced chemoresistance. Our data characterize the UPR in glioma cells and human tumors, and link the UPR to chemoresistance possibly via enhanced metabolism. Given the role of the UPR in the balance between cell survival and apoptosis, targeting the UPR and/or controlling metabolic activity may prove beneficial for malignant glioma therapeutics.
Details
- Title: Subtitle
- Induction of the unfolded protein response drives enhanced metabolism and chemoresistance in glioma cells
- Creators
- Laura M Epple - Department of Neurosurgery, Anschutz Medical Center, University of Colorado Denver, Aurora, Colorado, United States of AmericaRebecca D DoddAndrea L MerzAnjelika M DechkovskaiaMatthew HerringBenjamin A WinstonAlex M LencioniRae L RussellHelen MadsenMeheret NegaNathaniel L DustoJason WhiteDarell D BignerChristopher V NicchittaNatalie J SerkovaMichael W Graner
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.8(8), pp.e73267-e73267
- DOI
- 10.1371/journal.pone.0073267
- PMID
- 24039668
- PMCID
- PMC3748289
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science
- Grant note
- R25GM083333 / NIGMS NIH HHS UL1 RR025780 / NCRR NIH HHS P30 CA046934 / NCI NIH HHS R25 GM083333 / NIGMS NIH HHS
- Language
- English
- Date published
- 2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094617002771
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