title: Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.
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.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Man
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jocelyn D
authors.initials: JD
authors.lastname: Shoemake
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Tuopu
authors.initials: T
authors.lastname: Ma
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Rizzo
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Godley
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Alireza M
authors.initials: AM
authors.lastname: Mohammadi
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Shideng
authors.initials: S
authors.lastname: Bao
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio. Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio. yuj2@ccf.org.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yu
mesh_terms: D000818:Animals; D016923:Cell Death / Q000528:radiation effects; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000528:radiation effects; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects
chemical_list: D051058:Oncogene Protein v-akt