Modification of Cellular Response by Changes in Microenvironment Caused by Radiation-Induced Nitric Oxide Production and Mechanisms.

一氧化氮(NO)是一种多功能的生理物质。近年来，一氧化氮被认为参与了P53对热休克、电离辐射和细胞代谢变化等多种应激反应的依赖。为了验证这一假设，我们使用携带野生型或突变型p53基因的人胶质母细胞瘤细胞和鳞状细胞癌细胞，研究了热休克或辐射细胞内源性产生的一氧化氮对非应激细胞的影响。经热休克或辐射处理的供体细胞分泌的一氧化氮可通过诱导细胞内信号转导来调节受体细胞的温度或辐射敏感性。我们的发现在与处理过的NO供体细胞共培养的NO受体细胞中积累了P53和HSP72，这为通过NO作为中介而没有细胞间相互作用(如缝隙连接)的细胞间信号转导途径提供了第一个证据。提示NO是热休克或辐射等环境应激引起的旁观者效应的因素之一。综上所述，这些发现表明了由一氧化氮启动的细胞间信号转导通路在细胞对热休克或电离辐射对热疗或癌症放疗的反应中的重要性。

Nitric oxide(NO)is known to be a multi-functional physiological substance. Recently, nitric oxide is suggested to be involved in p53-dependent response to many kinds of stress such as heat shock, ionizing radiation and changes in cellular metabolism. To verify this hypothesis we examined the effect of nitric oxide produced endogenously by heat-shocked or irradiated cells on non-stressed cells using human glioblastoma cells and squamous cell carcinoma cells bearing either wild-type or mutant p53 gene. Nitric oxide excreted from the treated donor cells with heat-shock or radiation could modulate thermo-or radiosensitivity of recipient cells through induction of intracellular signal transduction. Our finding of the accumulation of p53 and hsp72 in NO-recipient cells co-cultivated with treated NO-donor cells provides the first evidence for an intercellular signal transduction pathway via NO as an intermediate without cell-to-cell interactions such as gap junctions. It is suggested that NO is one of factors for bystander effect induced by environmental stress such as heat-shock or radiation. Collectively, these findings indicate the importance of an intercellular signal transduction pathway intiated by nitric oxide in the cellular response to heat-shock or ionizing radiation on hyperthermia or radiotherapy of cancer.