Signaling the Unfolded Protein Response in primary brain cancers

Abstract

The Unfolded Protein Response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress in the Endoplasmic Reticulum (ER). During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply; exposure to chemotherapies) challenges, with which they must cope to survive. Primary brain tumors are relatively rare but deadly and present a significant challenge in the determination of risk factors in the population. These tumors are inherently difficult to cure because of their protected location in the brain. As such surgery, radiation and chemotherapy options carry potentially lasting patient morbidity and incomplete tumor cure. Some of these tumors, such as glioblastoma, were reported to present features of ER stress and to depend on UPR activation to sustain growth, but to date there is no clear general representation of the ER stress status in primary brain tumors. In this review, we describe the key molecular mechanisms controlling the UPR and their implication in cancers. Then we extensively review the literature reporting the status of ER stress in various primary brain tumors and discuss the potential impact of such observation on patient stratification and on the possibility of developing appropriate targeted therapies using the UPR as therapeutic target.

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…As such, a large number (>55) of small molecules have been tested on GBM cell lines and induced cell death by a mechanism that indirectly perturbs ER proteostasis, hence highlighting their potential use as therapeutic agents (149,150) [ Table 2 (22,(65)(66)(67)]. The impact of these molecules on ER proteostasis imbalance was in most cases (85%) inferred by the up-regulation of GRP78 and/or CHOP mRNA or protein abundance, but generally, the causality of ER stress in the cell death process was not demonstrated.…”

Novel IRE1-dependent proinflammatory signaling controls tumor infiltration by myeloid cells

“…The consequences of UPR signaling have been studied in various cancers such as breast, liver, lung, prostate, pancreas, and in glioblastoma multiforme (GBM), one of the most lethal and aggressive primary brain tumor with a median survival of 15-18 months despite invasive multimodal treatment (Le Reste et al, 2016). IRE1 contributes to GBM development by regulating tumor growth, migration, invasion and vascularization, partially through RIDDmediated cleavage of SPARC mRNA (Auf et al, 2010;Dejeans et al, 2012).…”

Regulation of tumor–stroma interactions by the unfolded protein response

“…It was also proposed that direct association of unfolded proteins to yeast and mammalian IRE1 could induce its activation through conformational change . Upon ER stress, ATF6 is exported from the ER to the Golgi apparatus, where it is activated by the SP1‐ and SP2‐medited proteolytic cleavage, which releases the cytosolic fragment of the protein, ATF6f . The latter is further translocated to the nucleus to regulate the transcription of genes involved in ER‐associated degradation (ERAD) and protein folding .…”

“…The overexpression of UPR sensors has been reported in a large number of human cancers including that of breast, brain, gastrointestinal tract, liver, kidney, pancreas, lung, and prostate . In addition, elevated level of the main UPR regulator GRP78 is often found in tumor tissues and is associated with metastasis, poor prognosis, and resistance to treatment .…”