Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme.
Jennifer P NewmanGrace Y WangKazuhiko ArimaShou P GuanMichael R WatersWebster K CaveneeEdward PanEdita AliwargaSiao T ChongCatherine Y L KokBerwini B EndayaAmyn A HabibTomohisa HoribeWai H NgIvy A W HoKam M HuiTomasz KordulaPaula Y P LamPublished in: Nature communications (2017)
The interleukin-13 receptor alpha2 (IL-13Rα2) 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-13Rα2 alone induces invasiveness of human GBM cells without affecting their proliferation. In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13Rα2 promotes GBM cell proliferation in vitro and in vivo. Mechanistically, the cytoplasmic domain of IL-13Rα2 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-13Rα2 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.
Keyphrases
- cell proliferation
- tyrosine kinase
- endothelial cells
- signaling pathway
- epidermal growth factor receptor
- small cell lung cancer
- binding protein
- induced apoptosis
- magnetic resonance
- pi k akt
- cell cycle
- multiple sclerosis
- cell death
- computed tomography
- blood brain barrier
- cell cycle arrest
- single molecule
- cell migration
- cancer therapy
- smoking cessation