The chemotherapeutic agent bortezomib induces the formation of stress granules

We show that bortezomib efficiently induces the formation of SGs in cancer cells. This process involves the phosphorylation of translation initiation factor eIF2α by heme-regulated inhibitor kinase (HRI). Depletion of HRI prevents bortezomib-induced formation of SGs and promotes apoptosis.This is the first study describing the formation of SGs by a chemotherapeutic compound. We speculate that the activation of HRI and the formation of SGs might constitute a mechanism by which cancer cells resist bortezomib-mediated apoptosis.The proteasome is a large multi-subunit complex responsible for the degradation of various proteins, including cell cycle regulators and apoptotic factors, by ubiquitin-dependent and -independent mechanisms [1,2]. Proteasome inhibitors are known to induce apoptosis in proliferating cells [3-6]. The proteasome inhibitor bortezomib is now FDA-approved and in clinical use against mantle cell myeloma and multiple myeloma, against which it displays strong anti-tumor activity [7-14]. However, solid tumors of various histological origins are refractory to bortezomib treatment, and this resistance is also observed in cancer cell lines derived from solid tumors in vitro [7,15-17]. The mechanisms by which cancer cells resist bortezomib are still largely unknown, although that this resistance is thought to involve the activation of a general stress response [7,15-17].When exposed to environmental stress, cells rapidly activate pathways generating a coordinated response involving mRNA translation and turnover, that confers protection against stress-induced damage and promotes their survival. Noxious conditions (e.g. heat shock, oxidative stress, UV radiations, viral infections, etc.) induce cellular arrest of translation initiation [18]. This translational block is largely due to phosphorylation of translation initiation factor eIF2α [19]. Under normal growth conditions, eIF2 associates with initiator Met-tRNAiMet (aminoacylated initiator methionyl-tRNA) an