Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme

Abstract

The interleukin-13 receptor alpha2 (IL-13R?2) is a cancer-associated receptor overexpressed in human glioblastoma multiforme (GBM). This receptor is undetectable in normal brain which makes it a highly suitable target for diagnostic and therapeutic purposes. However, the pathological role of this receptor in GBM remains to be established. Here we report that IL-13R?2 alone induces invasiveness of human GBM cells without affecting their proliferation. In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13R?2 promotes GBM cell proliferation in vitro and in vivo. Mechanistically, the cytoplasmic domain of IL-13R?2 specifically binds to EGFRvIII, and this binding upregulates the tyrosine kinase activity of EGFRvIII and activates the RAS/RAF/MEK/ERK and STAT3 pathways. Our findings support the "To Go or To Grow" hypothesis whereby IL-13R?2 serves as a molecular switch from invasion to proliferation, and suggest that targeting both receptors with STAT3 signaling inhibitor might be a therapeutic approach for the treatment of GBM. © 2017 The Author(s).