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

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Sci. Signal.  14 Mar 2017:
Vol. 10, Issue 470, eaal2323
DOI: 10.1126/scisignal.aal2323


Glioblastoma (GBM) is the most common and aggressive brain tumor. Standard care combines surgery, radiotherapy, and chemotherapy, but patient median survival does not exceed 15 months. The unfolded protein response (UPR) is an adaptive cellular signaling pathway that promotes restoration of endoplasmic reticulum proteostasis. The UPR plays instrumental roles in various cancers, particularly growth, invasion, therapeutic resistance, and angiogenesis in GBM. In this Review, which contains four figures, two tables, and 219 references, we discuss how adjuvant or neoadjuvant UPR-targeted compounds could impede GBM growth and increase the efficacy of current treatments.


Cellular stress induced by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) is a central feature of secretory cells and is observed in many tissues in various diseases, including cancer, diabetes, obesity, and neurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the cytosol and nucleus to restore proteostasis. In the past decade, ER stress has emerged as a major pathway in remodeling gene expression programs that either prevent transformation or provide selective advantage in cancer cells. Controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, UPR signaling is a highly regulated process that leads to an integrated reprogramming of the cell. In this Review, we provide an overview of the regulatory mechanisms underlying UPR signaling and how this pathway modulates cancer progression, particularly the aggressiveness and chemotherapeutic resistance exhibited by glioblastoma, a form of brain cancer. We also discuss the emerging cross-talk between the UPR and related metabolic processes to ensure maintenance of proteostasis, and we highlight possible therapeutic opportunities for targeting the pathway with small molecules.

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