TY - JOUR
T1 - Hyperthermia sensitizes Glioma stem-like cells to radiation by inhibiting AKT signaling
AU - Man, Jianghong
AU - Shoemake, Jocelyn D.
AU - Ma, Tuopu
AU - Rizzo, Anthony E.
AU - Godley, Andrew R.
AU - Wu, Qiulian
AU - Mohammadi, Alireza M.
AU - Bao, Shideng
AU - Rich, Jeremy N.
AU - Yu, Jennifer S.
N1 - Publisher Copyright:
© 2015 AACR.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/4/15
Y1 - 2015/4/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-14-3621
DO - 10.1158/0008-5472.CAN-14-3621
M3 - Article
C2 - 25712125
AN - SCOPUS:84942929160
VL - 75
SP - 1760
EP - 1769
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 8
ER -