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

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

doi:10.1038/s41467-017-01392-9

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

Nat Commun. 2017 Dec 4;8(1):1913. doi: 10.1038/s41467-017-01392-9.

Authors

Jennifer P Newman¹, Grace Y Wang^{1

2}, Kazuhiko Arima³, Shou P Guan¹, Michael R Waters⁴, Webster K Cavenee⁵, Edward Pan⁶, Edita Aliwarga¹, Siao T Chong¹, Catherine Y L Kok¹, Berwini B Endaya⁷, Amyn A Habib⁸, Tomohisa Horibe⁹, Wai H Ng¹⁰, Ivy A W Ho^{1

10}, Kam M Hui^{11

12

13

14}, Tomasz Kordula⁴, Paula Y P Lam^{15

16

17}

Affiliations

¹ Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11, Hospital Drive, Singapore, 169610, Singapore.
² Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA, 94609, USA.
³ Department of Biomolecular Sciences, Saga Medical School, Saga, 840-8502, Japan.
⁴ School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
⁵ Ludwig Institute for Cancer Research, San Diego, CA, 92093, USA.
⁶ Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
⁷ School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222, Queensland, Australia.
⁸ Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center and the North Texas VA Medical Center, Dallas, 75390, USA.
⁹ Department of Pharmacoepidemiology, Kyoto University School of Public Health, Kyoto, 606-8501, Japan.
¹⁰ National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.
¹¹ Bek Chai Heah Laboratory of Cancer Genomics, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, 169610, Singapore.
¹² Cancer and Stem Cells Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singapore.
¹³ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Dr, Singapore, 117596, Singapore.
¹⁴ Institute of Molecular and Cell Biology, A*STAR, Proteos, 61 Biopolis Dr, Singapore, 138673, Singapore.
¹⁵ Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11, Hospital Drive, Singapore, 169610, Singapore. [email protected].
¹⁶ Cancer and Stem Cells Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singapore. [email protected].
¹⁷ Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, MD9, Singapore, 117593, Singapore. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding