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

Abstract

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.

• Authors: Jennifer P Newman, Grace Y Wang, Kazuhiko Arima, Shou P Guan, Michael R Waters, Webster K Cavenee, Edward Pan, Edita Aliwarga, Siao T Chong, Catherine Y L Kok, Berwini B Endaya, Amyn A Habib, Tomohisa Horibe, Wai H Ng, Ivy A W Ho, Kam M Hui, Tomasz Kordula, Paula Y P Lam
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 1913 (12 04 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29203859 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Interleukin-13 Receptor alpha2 Subunit
• RNA, Messenger
• epidermal growth factor receptor VIII
• ErbB Receptors
• raf Kinases
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase Kinases
• ras Proteins

Topics

• Animals
• Brain Neoplasms (genetics, metabolism, mortality, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• ErbB Receptors (genetics)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Knockdown Techniques
• Glioblastoma (genetics, metabolism, mortality, pathology)
• Humans
• In Vitro Techniques
• Interleukin-13 Receptor alpha2 Subunit (genetics, metabolism)
• MAP Kinase Kinase Kinases (metabolism)
• Mice
• Mutation
• Neoplasm Invasiveness (genetics)
• Neoplasm Transplantation
• RNA, Messenger (metabolism)
• Survival Rate
• raf Kinases (metabolism)
• ras Proteins (metabolism)