%0 Journal Article
%T The chemotherapeutic agent bortezomib induces the formation of stress granules
%A Marie-Jos¨¦e Fournier
%A Cristina Gareau
%A Rachid Mazroui
%J Cancer Cell International
%D 2010
%I BioMed Central
%R 10.1186/1475-2867-10-12
%X We show that bortezomib efficiently induces the formation of SGs in cancer cells. This process involves the phosphorylation of translation initiation factor eIF2¦Á 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 eIF2¦Á [19]. Under normal growth conditions, eIF2 associates with initiator Met-tRNAiMet (aminoacylated initiator methionyl-tRNA) an
%U http://www.cancerci.com/content/10/1/12