Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation

Yuanying Gong, Yufang Ma, Maksim Sinyuk, Sudan Loganathan, Reid C. Thompson, Jann N. Sarkaria, Wenbiao Chen, Justin D. Lathia, Bret C. Mobley, Stephen W. Clark, Jialiang Wang

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Background Metabolic complications such as obesity, hyperglycemia, and type 2 diabetes are associated with poor outcomes in patients with glioblastoma. To control peritumoral edema, use of chronic high-dose steroids in glioblastoma patients is common, which can result in de novo diabetic symptoms. These metabolic complications may affect tumors via profound mechanisms, including activation of insulin receptor (InsR) and the related insulin-like growth factor 1 receptor (IGF1R) in malignant cells. Methods In the present study, we assessed expression of InsR in glioblastoma surgical specimens and glioblastoma response to insulin at physiologically relevant concentrations. We further determined whether genetic or pharmacological targeting of InsR affected oncogenic functions of glioblastoma in vitro and in vivo. Results We showed that InsR was commonly expressed in glioblastoma surgical specimens and xenograft tumor lines, with mitogenic isoform-A predominating. Insulin at physiologically relevant concentrations promoted glioblastoma cell growth and survival, potentially via Akt activation. Depletion of InsR impaired cellular functions and repressed orthotopic tumor growth. The absence of InsR compromised downstream Akt activity, but yet stimulated IGF1R expression. Targeting both InsR and IGF1R with dual kinase inhibitors resulted in effective blockade of downstream signaling, loss of cell viability, and repression of xenograft tumor growth. Conclusions Taken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.

Original languageEnglish (US)
Pages (from-to)48-57
Number of pages10
JournalNeuro-oncology
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • Akt
  • IGF1R
  • glioblastoma
  • insulin
  • insulin receptor

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Gong, Y., Ma, Y., Sinyuk, M., Loganathan, S., Thompson, R. C., Sarkaria, J. N., Chen, W., Lathia, J. D., Mobley, B. C., Clark, S. W., & Wang, J. (2016). Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation. Neuro-oncology, 18(1), 48-57. https://doi.org/10.1093/neuonc/nov096