Hyperthermia sensitizes Glioma stem-like cells to radiation by inhibiting AKT signaling

Jianghong Man, Jocelyn D. Shoemake, Tuopu Ma, Anthony E. Rizzo, Andrew R. Godley, Qiulian Wu, Alireza M. Mohammadi, Shideng Bao, Jeremy N. Rich, Jennifer S. Yu

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment.

Original languageEnglish (US)
Pages (from-to)1760-1769
Number of pages10
JournalCancer research
Volume75
Issue number8
DOIs
StatePublished - Apr 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Man, J., Shoemake, J. D., Ma, T., Rizzo, A. E., Godley, A. R., Wu, Q., Mohammadi, A. M., Bao, S., Rich, J. N., & Yu, J. S. (2015). Hyperthermia sensitizes Glioma stem-like cells to radiation by inhibiting AKT signaling. Cancer research, 75(8), 1760-1769. https://doi.org/10.1158/0008-5472.CAN-14-3621