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

本研究旨在探讨肿瘤缺氧、肿瘤细胞与细胞外基质相互作用等肿瘤环境引起的信号转导通路激活的作用，研究结果表明，急性肿瘤缺氧或肿瘤细胞与细胞外基质相互作用引起的生存信号转导激活降低了癌细胞的放射敏感性，表皮生长因子对细胞外生存信号转导通路的刺激也能减少辐射诱导的细胞凋亡。抑制这些信号转导的激活增强了具有野生型或突变型p53基因的各种癌细胞的辐射诱导的细胞杀伤。这些结果表明，内源性和外源性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抗性有关。在关于表观遗传因素如组蛋白乙酰化对放射敏感性的作用的分析中，我们发现，组蛋白去乙酰化酶（HDAC）抑制剂引起的组蛋白过度乙酰化与辐射联合作用，通过p53-独立的凋亡诱导。在该机制中，Hsp 90的乙酰化也通过减少Hsp 90与客户蛋白（包括Raf-1或Akt）的结合而涉及。进一步的研究需要探索确定放射敏感性的分子靶点，因为增强辐射诱导的细胞杀伤将为临床癌症治疗提供巨大的优势。

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.