Molecular target for radiation-induced cell killing that are associated with tumor microenvironment

与肿瘤微环境相关的辐射诱导细胞杀伤的分子靶标

• 批准号: 13670916
• 负责人: AKIMOTO Tetsuo
• 金额: $ 2.3万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670916/
• 关键词: Radiosensitivity; Molecular target; radiation; tumor microenvironment; survival signal; 生存シグナル伝達; 放射線治療; 増感作用; 低酸素; アポトーシス; 細胞外マトリックス; 増殖因子

The purpose of this research project is to explore the role of activation of the signal transduction pathway originated from tumor environment including tumor hypoxia, interaction between tumor cell and extracellular matrix, and so on. The results of this research project revealed that activation of survival signal transduction induced by acute tumor hypoxia or interaction between tumor cell and extracellular matrix decreased radiosensitivity of cancer cells, and Extracellular stimulation of the survival signal transduction pathways using epidermal growth factor also decreased radiation-induced apoptosis. Inhibition of activation of these signal transduction enhanced radiation-induced cell killing in variety cancer cells that have wild or mutant p53 gene. These results indicated that activation the survival signal transduction pathways induced by intrinsic and extrinsic factors may be associated with radioresistant profile of cancer cells.In the analysis regarding the role of epigenetic factors such as acetylation of histone on radiosensitivity, we found that hyperacetylation of histone by histone deacetylase (HDAC) inhibitor combined with radiation greatly enhanced radiation-induced cell killing through p53-independent apoptosis induction. In this mechanism, acetylation of Hsp90 was also involved by reducing binding of Hsp90 to client proteins including Raf-1 or Akt. Further research is needed to explore the molecular targets for determination of radiosensitivity, because enhancement of radiation-induced cell killing would provide great advantage for cancer treatment in clinics.

本研究项目的目的是探讨源自肿瘤环境的信号转导通路激活的作用，包括肿瘤缺氧、肿瘤细胞与细胞外基质的相互作用等。该研究项目的结果表明，急性肿瘤缺氧或肿瘤细胞与细胞外基质之间的相互作用诱导的生存信号转导激活降低了癌细胞的放射敏感性，并且利用表皮生长因子对生存信号转导途径的细胞外刺激也降低了放射敏感性。细胞凋亡。在具有野生或突变 p53 基因的各种癌细胞中，抑制这些信号转导的激活可增强辐射诱导的细胞杀伤作用。这些结果表明，内在和外在因素诱导的生存信号转导通路的激活可能与癌细胞的放射抵抗特性有关。在分析组蛋白乙酰化等表观遗传因素对放射敏感性的作用时，我们发现组蛋白的过度乙酰化通过组蛋白脱乙酰酶 (HDAC) 抑制剂与辐射相结合，通过 p53 独立的细胞凋亡诱导，大大增强了辐射诱导的细胞杀伤作用。在此机制中，Hsp90 的乙酰化还通过减少 Hsp90 与客户蛋白（包括 Raf-1 或 Akt）的结合来参与。需要进一步的研究来探索确定放射敏感性的分子靶点，因为增强放射诱导的细胞杀伤将为临床癌症治疗提供巨大优势。

项目成果

Akimoto T, Muramatsu H, Takahashi M, Saitoh J, Kitamoto Y, Miyazawa Y, Yamada M, Ito K, Kurokawa K, Yamanaka H, Nakano T, Mitsuhashi N, Niibe H.: "Rectal bleeding after hypofractionated radiotherapy for prostate cancer : Correlation between clinical and d

Akimoto T、Muramatsu H、Takahashi M、Saitoh J、Kitamoto Y、Miyazawa Y、Yamada M、Ito K、Kurokawa K、Yamanaka H、Nakano T、Mitsuhashi N、Niibe H.：“前列腺癌大分割放射治疗后直肠出血：

Kitamoto Y, Sakurai H, Mitsuhashi N, Akimoto T, Nakano T: "Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line."Cancer Letters. 191(1). 2741-2747 (2003)

Kitamoto Y、Sakurai H、Mitsuhashi N、Akimoto T、Nakano T：“咖啡因可减弱紫杉醇对人肺腺癌细胞系的细胞毒性作用。”《癌症快报》。

Nonaka T: "Changes in the localization of heat shock protein 72 correlated with development of thermotolerance in human esophageal cancer cell line."AntiCancer Res. 23(6C). 4677-4687 (2003)

Nonaka T：“热休克蛋白 72 定位的变化与人类食管癌细胞系耐热性的发展相关。”AntiCancer Res。

Tetsuo Akimoto, Tetsuo Nonaka, Hideyuki Sakurai, Norio Mitsuhashi: "Heat shock protein 90 chaperone complex : A molecular target for enhancement of thermosensitivity and radiosensitivity"Jpn J Hyperthermia. 18(3). 131-141 (2002)

Tetsuo Akimoto、Tetsuo Nonaka、Hideyuki Sakurai、Norio Mitsuhashi：“热休克蛋白 90 伴侣复合物：增强热敏感性和放射敏感性的分子靶标”Jpn J Hyperthermia。

Sakurai H, Mitsuhashi N, Takahashi M, Akimoto T, Muramatsu H, Ishikawa H, Imai R, Yamakawa M, Hasegawa M, Niibe H.: "Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone : patterns of recurrence,

Sakurai H、Mitsuhashi N、Takahashi M、Akimoto T、Muramatsu H、Ishikawa H、Imai R、Yamakawa M、Hasekawa M、Niibe H.：“单纯放射治疗后宫颈鳞状细胞癌复发的分析：模式