The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma

Abstract

Therapeutic resistance is a major barrier to improvement of outcomes for patients with glioblastoma. The endoplasmic reticulum stress response (ERSR) has been identified as a contributor to chemoresistance in glioblastoma; however the contributions of the ERSR to radioresistance have not been characterized. In this study we found that radiation can induce ER stress and downstream signaling associated with the ERSR. Induction of ER stress appears to be linked to changes in ROS balance secondary to irradiation. Furthermore, we observed global induction of genes downstream of the ERSR in irradiated glioblastoma. Knockdown of ATF6, a regulator of the ERSR, was sufficient to enhance radiation induced cell death. Also, we found that activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1. Our results reveal ATF6 as a potential therapeutic target to enhance the efficacy of radiation therapy.

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

“…However, no evidence has been reported so far that PERK promotes GBM angiogenesis and invasion. Recently, the involvement of the ATF6 arm of the UPR has been described in GBM resistance to radiation (77). Irradiation of GBM cells leads to UPR induction with a clear involvement of ATF6-dependent up-regulation of GRP78 and NOTCH1 (77).…”

“…Recently, the involvement of the ATF6 arm of the UPR has been described in GBM resistance to radiation (77). Irradiation of GBM cells leads to UPR induction with a clear involvement of ATF6-dependent up-regulation of GRP78 and NOTCH1 (77). Moreover, a high-resolution clustered regularly interspaced short palindromic repeats (CRISPR) screen in GBM stem-like cells has also revealed the involvement of ATF6 branch of the UPR in glioma development (78).…”

“…Collectively, these results indicate that ER proteostasis might be an important factor in GBM cells' sensitivity to irradiation. The ATF6 arm of the UPR contributes to irradiation resistance in GBM cells (77). A more detailed and systematic analysis of the contribution of the three arms of the UPR in GBM progression is still required.…”

ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation

“…The significance of the ER-dependent pathways to cancer development also extends to clinical applications [13, 14]. Several anticancer agents also generate survival responses through activation of the unfolded protein response [15].…”

Signaling the Unfolded Protein Response in primary brain cancers

“…Moreover, the PERK pathway has also been involved in the control of GBM cells metabolism (Hou et al, 2015) and response to treatment Yacoub et al, 2010). Finally, the ATF6 pathway was recently reported to contribute to GBM resistance to radiotherapy (Dadey et al, 2015) (Figure 2). b) Lower-grade tumors -Lower-grade astrocytomas (WHO Grade I/II) constitute a heterogeneous group of tumors mostly represented by oligodendrogliomas and astrocytomas, the classification and prognostic indicators of which being completely transformed by molecular diagnosis (Weller et al, 2015).…”