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.