Autocrine control of glioma cells adhesion/migration through Inositol Requiring enzyme 1α (IRE1α)-mediated cleavage of Secreted Protein Acidic Rich in Cysteine (SPARC) mRNA

Abstract

The endoplasmic reticulum (ER) is an organelle specialized for the folding and assembly of secretory and transmembrane proteins. ER homeostasis is often perturbed in tumor cells due to dramatic changes in solid tumor microenvironment, thereby leading to the activation of an adaptive mechanism named the Unfolded Protein Response (UPR). The activation of the UPR sensor IRE1α has been described to play an important role in tumor progression. However, the molecular events associated with this phenotype remain poorly characterized. In the present study, we examined the effects of IRE1α signaling on glioma cells adaptation to their microenvironment. We show that the characteristics of U87 cells migration are modified under conditions where IRE1α activity is impaired (DN_IRE1). This is linked to increased stress fiber formation and enhanced RhoA activity. Gene expression profiling also revealed that loss of functional IRE1α signaling mostly resulted in the up-regulation of genes encoding extracellular matrix proteins. Among these genes, SPARC, whose mRNA is a direct target of IRE1α endoribonuclease activity, was in part responsible for the phenotypic changes associated with IRE1α inactivation. Hence, our data demonstrate that IRE1α is a key regulator of SPARC expression in vitro in a glioma model. Our results also further support the critical role of IRE1α contribution to tumor growth and infiltration/invasion and extend the paradigm of secretome control in tumor microenvironment conditioning.