Zhang Li, Subarsky Patrick, Hill Richard P
Research Division, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Ontario, Canada.
Int J Radiat Biol. 2007 Jul;83(7):443-56. doi: 10.1080/09553000701373708.
To determine the response of tumor suppressor p53 to hypoxia in different tumor cell lines and the involvement of p53 activity regulation in the effect of hypoxia on tumor cell sensitivity to radiation and hyperthermia.
Three tumor cell lines with functional p53 were treated with chronic or cyclic hypoxia followed by radiation or hyperthermia to investigate p53 activity and cell survival. Flow cytometry was used to investigate the effect of hypoxia-induced cell cycle arrest on radiosensitivity in KHT-C (mouse fibrosarcoma) cells. Transient transfection was performed to determine the role of altered p53 activity in KHT-C and SCC VII (mouse squamous-cell carcinoma) radiosensitivity.
Aerobic radiosensitivity was decreased in KHT-C and SCC VII cells after in vitro chronic or cyclic hypoxia pretreatment, but in HT1080 cells, it was slightly increased after chronic hypoxia, and was unchanged after acute hypoxia pretreatment. Decreased radiosensitivity in hypoxia-pretreated KHT-C and SCC VII cells was unlikely due to hypoxia-induced cell cycle arrest, but rather seemed to be associated with increased expression of Mdm2 (mouse double minute-2) and decreased p53. Furthermore, hypoxia pretreatment inhibited the activation of p53 by radiation. Similar results were observed in hyperthermia treated KHT-C cells. Finally, decreased radiosensitivity was observed in both KHT-C and SCC VII cells transiently transfected with Mdm2 or anti-sense p53 cDNA.
We demonstrated that hypoxia may decrease tumor cell radiosensitivity through the suppression of p53 activity in some tumor cell lines. These results suggested the response of p53 to hypoxia can be cell type specific and contribute to radiosensitivity of hypoxic cells.
确定肿瘤抑制因子p53在不同肿瘤细胞系中对缺氧的反应，以及p53活性调节在缺氧对肿瘤细胞辐射和热疗敏感性影响中的作用。
对三种具有功能性p53的肿瘤细胞系进行慢性或周期性缺氧处理，随后进行辐射或热疗，以研究p53活性和细胞存活情况。采用流式细胞术研究缺氧诱导的细胞周期阻滞对KHT-C（小鼠纤维肉瘤）细胞放射敏感性的影响。进行瞬时转染以确定p53活性改变在KHT-C和SCC VII（小鼠鳞状细胞癌）放射敏感性中的作用。
体外慢性或周期性缺氧预处理后，KHT-C和SCC VII细胞的需氧放射敏感性降低，但在HT1080细胞中，慢性缺氧后放射敏感性略有增加，急性缺氧预处理后则无变化。缺氧预处理的KHT-C和SCC VII细胞放射敏感性降低不太可能是由于缺氧诱导的细胞周期阻滞，而似乎与Mdm2（小鼠双微体2）表达增加和p53减少有关。此外，缺氧预处理抑制了辐射对p53的激活。在热疗处理的KHT-C细胞中也观察到了类似结果。最后，用Mdm2或反义p53 cDNA瞬时转染的KHT-C和SCC VII细胞均出现放射敏感性降低。
我们证明，在某些肿瘤细胞系中，缺氧可能通过抑制p53活性降低肿瘤细胞放射敏感性。这些结果表明，p53对缺氧的反应具有细胞类型特异性，并有助于缺氧细胞的放射敏感性。
