Salubrinal inhibits glioma growth and sensitizes malignant gliomas to ER stress- and Temozolomide-induced death

Glioblastoma multiforme represents a particularly difficult-to-treat type of cancer with a dismal prognosis. Recent studies showed that human malignant gliomas adapt to their local cellular environments by triggering the endoplasmic reticulum (ER) stress response. This response not only activates critical adaptive pathways for cell survival but also switches to apoptosis when ER stress signaling is prolonged or excessive. Therefore, approaches that either down-regulate the protective ER stress response or enhance ER stress signaling in malignant gliomas may significantly improve treatment outcome. Here we report that Salubrinal (Sal), an inhibitor of phospho-eukaryotic translation initiation factor (p-eIF2α) dephosphorylation, impedes glioma proliferation and invasiveness. The anti-tumorigenic properties of Sal are associated with impaired receptor-mediated calcium signaling resulting from the down-regulation of the ER-resident calcium release channel protein, inositol triphosphate receptor (IP3R). We als...