Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.
Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.
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DOI：
10.1158/0008-5472.can-14-3621
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发表时间：
2015-04-15
期刊：
影响因子：
11.2
通讯作者：
Yu JS
中科院分区：
文献类型：
--
作者：
Man J;Shoemake JD;Ma T;Rizzo AE;Godley AR;Wu Q;Mohammadi AM;Bao S;Rich JN;Yu JS
胶质瘤干细胞样细胞（GSC）是肿瘤中的细胞亚群，被认为介导胶质母细胞瘤（GBM）的自我更新和复发，胶质母细胞瘤是原发性脑癌的最致命形式。在放射肿瘤学中，已知热疗可使细胞放射增敏，并且它重新成为GBM患者的治疗选择。在这项研究中，我们研究了热辐射增敏GSCs的磷酸激酶阵列，揭示了生存激酶AKT作为一个关键的敏化决定因素的机制。单独用放射治疗的GSC表现出增加的AKT活化，但在放射治疗前添加热疗降低了AKT活化并损害了GSC增殖。在GSC中引入组成型活性AKT会损害热辐射增敏作用。PI3K的药理学抑制进一步增强了热疗的放射增敏作用。在人GBM的临床前原位移植模型中，热放疗降低了pS6水平，延迟了肿瘤生长并延长了动物存活期。总之，我们的研究结果提供了一个临床前的概念验证，进一步评估联合热疗和辐射治疗GBM。
Glioma stem-like cells (GSCs) 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 re-emerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phosphokinase 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.