Translocon-regulated ER proteostasis in glioblastoma

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Abstract Glioblastoma multiforme (GBM) remains refractory to current standard-of-care treatment and is associated with a bleak prognosis and poor quality of life in the final months. Endoplasmic reticulum (ER) stress, and consequently a constitutive activation of the unfolded protein response (UPR), is a common feature of GBM and has been linked to increased aggressiveness and therapeutic resistance. The Sec61 translocon is a protein-conducing channel which spans the ER membrane and is essential for cotranslocational translocation of client proteins. Sec61 subunits are also upregulated by ER stress in GBM and the gene encoding the gamma subunit (SEC61G) is considered a GBM proto-oncogene. We now present evidence that Sec61 is directly implicated in ER stress/UPR signaling in GBM cancer stem cells (GSCs). Overall, our results suggest that pharmacological inactivation of Sec61 results in depletion of BiP mRNA levels and prevents pro- survival UPR signaling particularly through the UPR sensor inositol-requiring enzyme 1 (IRE1). Our central hypothesis is that Sec61 translocon is an essential regulator of UPR signaling and proteostasis in GBM. We will test this hypothesis through the following specific aims: 1) Define the role of Sec61 in UPR signaling in GBM. 2) Evaluate the therapeutic potential of pharmacological targeting Sec61 in orthotopic GSCs mouse models. This multidimensional approach will reveal the tumor-supportive properties of Sec61 translocon in GBM and GSCs and explore the feasibility of safely targeting Sec61 for therapeutic advantage while avoiding toxicities due to non-specific inhibition of secretory protein biosynthesis. This early stage pre-clinical research is expected to inform the future advancement of newly designed synthetic Sec61 inhibitors for the treatment of GBM and other aggressive human cancers characterized by high levels of adaptive ER stress.