αvβ3 and αvβ5 integrins control glioma cell response to ionising radiation through ILK and RhoB
αvβ3 and αvβ5 integrins control glioma cell response to ionising radiation through ILK and RhoB
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DOI：
10.1002/ijc.23498
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发表时间：
2008-07-15
影响因子：
6.4
通讯作者：
Toulas, Christine
中科院分区：
文献类型：
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作者：
Monferran, Sylvie;Skuli, Nicolas;Toulas, Christine
整合素是参与肿瘤侵袭和血管生成的细胞外基质受体。虽然有证据表明抑制整合素可以提高放射治疗的效率，但对整合素依赖的肿瘤放射敏感性调节的确切机制知之甚少。本研究的目的是探讨整合素αvβ3和αvβ5整合素在胶质母细胞瘤细胞辐射抗性中的作用，并破译其下游的生物学途径。我们首次证明了用特定的siRNAs沉默αvβ3和αvβ5整合素显著降低了2种胶质母细胞瘤细胞系U87和SF763照射后的存活率。然后，我们发现整合素活性和整合素信号通路控制着胶质瘤细胞的放射敏感性。这种对胶质瘤细胞对电离辐射的反应的调节是通过整合素连接的激酶ILK和小的GTP酶RhoB两种机制来调节的。第一个独立于ILK，存在于αvβ3或αvβ5整合素对RhoB细胞内水平的调节。参与细胞辐射敏感性的第二条途径是通过ILK电离辐射激活RhoB。此外，我们还证实了αvβ3/αvβ5整合素/ILK/RhoB通路通过调节辐射诱导的有丝分裂细胞死亡来控制胶质瘤细胞的放射敏感性。这项工作确定了一条控制胶质母细胞瘤细胞辐射抗性的新生物途径，该途径通过ILK和RhoB从细胞膜通过αvβ3和/或αvβ5整合素激活。我们的结果提示，αvβ3和αvβ5整合素的下游效应物，如ILK和RhoB，也可能成为提高放射治疗效率的候选靶点，从而改善胶质母细胞瘤患者的临床结果。(C)2008年Wiley-Liss，Inc.
Integrins are extracellular matrix receptors involved in tumour invasion and angiogenesis. Although there is evidence that inhibiting integrins might enhance the efficiency of radiotherapy, little is known about the exact mechanisms involved in the integrin-dependent modulation of tumor radiosensitivity. The purpose of this study was to investigate the role of alpha v beta 3 and alpha v beta 5 integrins in glioblastoma cell radioresistance and overall to decipher the downstream biological pathways. We first demonstrated that silencing alpha v beta 3 and alpha v beta 5 integrins with specific siRNAs significantly reduced the survival after irradiation of 2 glioblastoma cell lines: U87 and SF763. We then showed that integrin activity and integrin signalling pathways controlled the glioma cell radiosensitivity. This regulation of glioma cell response to ionising radiation was mediated through the integrin-linked kinase, ILK, and the small GTPase, RhoB, by two mechanisms. The first one, independent of ILK, consists in the regulation of the intracellular level of RhoB by alpha v beta 3 or alpha v beta 5 integrin. The second pathway involved in cell radiosensitivity consists in RhoB activation by ionising radiation through ILK. Furthermore, we demonstratead that the alpha v beta 3/alpha v beta 5 integrins/ILK/ RhoB pathway controlled the glioma cells radiosensitivity by regulating radiation-induced mitotic cell death. This work identifies a new biological pathway controlling glioblastoma cells radioresistance, activated from the membrane through alpha v beta 3 and/or alpha v beta 5 integrins via ILK and RhoB. Our results are clues that downstream effectors of alpha v beta 3 and alpha v beta 5 integrins as ILK and RhoB might also be promising candidate targets for improving the efficiency of radiotherapy and thus the clinical outcome of patients with glioblastoma. (C) 2008 Wiley-Liss, Inc.