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THE INVOLVEMENT OF OXIDANT AND ANTIOXIDANT SYSTEM IN FAS-MEDIATED APOPTOSIS OF ATL CELLS.

氧化剂和抗氧化剂系统参与 FAS 介导的 ATL 细胞凋亡。

基本信息

批准号：
07671214
负责人：
YAMADA Yasuaki
金额：
$ 1.54万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671214/
关键词：
ATL APOPTOSIS CD95 FAS OXIDANT ANTIOXIDANT GLUTATHIONE 8-OHdG GSH ceramide γ-GCS

项目摘要

The mechanism of Fsa (CD95)-mediated apoptosis of ATL cells was studied in the context of oxidant and antioxidant system. We established several ATL cell lines, which were sensitive or resistant to anti-Fas IgM monoclonal antibody.Although the addition of anti-Fas resulted in formation of oxygen radical species in the sensitive ce11s, no oxygen radical was produced from the resistant cells. The oxygen radical induced DNA damage as determined by formation of 8-hydroxydeoxyguanosine (8-OHdG), which showed a mutual relation with oxygen radical production. The resistant cells had two to three times higher amounts of intracellular glutathione (GSH) as antioxidant and gamma-glutamylcysteine synthetase (gamma-GCS) as the key enzyme for GSH synthesis than the sensitive cells. Interestingly, Fas-resistant cells showed cross resistance to antineoplastic drugs. Moreover, the urine samples from ATL patients showed transient increase of 8-OHdG after chemotherapy suggesting that antineoplastic agents also use oxidant for cell killing.However, since the addition of exogenous GSH did not abrogate the Fas-induced apoptosis, the involvement of protective machanism other than antioxidant was suggested. By the molecular analysis of Fas genes of resistant cells, we found that one of the cell line had a deletion of the gene for death domain.

从氧化和抗氧化系统的角度研究了Fsa（CD 95）介导的ATL细胞凋亡的机制。我们建立了几种对抗Fas IgM单克隆抗体敏感或耐药的ATL细胞系，虽然抗Fas抗体的加入导致敏感细胞产生氧自由基，但耐药细胞不产生氧自由基。氧自由基引起的DNA损伤是通过8-羟基脱氧鸟苷（8-OHdG）的形成来确定的，这与氧自由基的产生是相互关联的。耐药细胞的细胞内谷胱甘肽（GSH）作为抗氧化剂和γ-谷氨酰半胱氨酸合成酶（γ-GCS）作为GSH合成的关键酶比敏感细胞高2至3倍。有趣的是，Fas耐药细胞显示出交叉耐药的药物。化疗后8-OHdG的一过性升高提示抗肿瘤药物也有氧化作用，但外源性GSH的加入并不能消除Fas诱导的细胞凋亡，提示抗肿瘤药物的保护机制可能与抗氧化剂无关。通过对耐药细胞Fas基因的分子生物学分析，发现其中一株耐药细胞存在死亡结构域基因的缺失。