MODIFICATION OF RADIOSENSITIVITY BY ALTERATION OF ACTIVITY OF RECEPTOR TYROSINE KINASE AND ITS SIGNAL TRANSDUCTION PATHWAYS

通过改变受体酪氨酸激酶的活性及其信号转导途径来改变放射敏感性

• 批准号: 11670867
• 负责人: AKIMOTO Tetsuo
• 金额: $ 1.79万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670867/
• 关键词: Radiation; Survival signal transduction; Molecular-target therapy; MAP kinase; Apoptosis; p53; EGFR; 増殖因子受容体; 放射線感受性; 生存シグナル; シグナル伝達; MAPK; 細胞周期; Radiation; Survival signal transduction; Molecular-target therapy; MAP kinase; Apoptosis; p53; EGFR; 増殖因子受容体; 放射線感受性; 生存シグナル; シグナル伝達; MAPK; 細胞周期

The purpose of this study is to clarify the role of activation of receptor tyrosine kinase and its signal transduction pathways in determining radiosensitivity and enhancement of radiosensitivity. We have already reported that inverse relationship between EGFR expression and radiocurability in murine tumors, and the underline mechanism is in part attributed to activation of signal transduction pathways by radiation. In addition, we focused on "survival signal transduction pathways" that is consisted of Raf-MEK-p42/p44 ERK and PI3K-AKT/PKB, and a part of the results has already been reported. (1) Radiation activated survival signal transduction pathways, (2) Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity by inhibition of radiation-induced activation of survival signal transduction, (3) Selective inhibition of PI3K or p42/p44 ERK enhanced radiosensitivity, (4) Apoptosis induction may be involved in enhancement of radiosensitivity especially in the cell lines with wild type p53. These results indicated that survival signal transduction pathways plays an important role in determining radiosensitivity, and would be a molecular-target in improving treatment efficacy in radioresistant tumors.

这项研究的目的是阐明受体酪氨酸激酶的激活及其信号转导途径在确定放射敏感性和增强放射敏感性方面的作用。我们已经报道说，鼠肿瘤中EGFR表达与放射性性的反比关系，下划线机制部分归因于辐射通过辐射激活信号转导途径。此外，我们专注于由RAF-MEK-P42/P44 ERK和PI3K-AKT/PKB组成的“存活信号转导途径”，并且已经报道了一部分结果。 （1）辐射激活的生存信号转导途径，（2）酪氨酸激酶抑制剂染料木黄酮通过抑制辐射诱导的生存信号转导的激活来增强放射性敏感性，（3）选择性抑制PI3K或P42/P44 ERK的（增强的辐射率）尤其涉及辐射率（4）APOPTION（4）APOPTISE（4）APOPTOSIS（4）APOPTOSIS（4）野生型p53的线。这些结果表明，生存信号转导途径在确定放射敏感性方面起着重要作用，并且将是提高辐射耐药性肿瘤治疗功效的分子目标。