Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis
Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis
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DOI：
10.1053/gast.2002.34209
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发表时间：
2002-07-01
期刊：
影响因子：
29.4
通讯作者：
Johnson, LR
中科院分区：
文献类型：
--
作者：
Deng, WL;Balazs, L;Johnson, LR
背景与目的：研究磷脂生长因子溶血磷脂酸（LPA）对肠上皮细胞-6 （IEC-6）凋亡的抑制作用。并在小鼠辐射诱导细胞凋亡模型中检测了LPA的抗凋亡作用。方法：采用血清停药、喜树碱、t照射或大鼠肿瘤坏死因子α诱导细胞凋亡，并采用DNA片段酶联免疫吸附试验（ELISA）和膜联蛋白V染色评价细胞凋亡。ELISA法和Western blotting法分别检测Caspase-3/CPP32活性和活化程度。应用逆转录聚合酶链反应（RT-PCR）检测lpa受体转录物的表达。以1 mmol/L LPA浓度为250 mmol/L的il处理小鼠，12 Gy或15 Gy全身t照射，记录沿隐窝凋亡小体的数量和定位。结果：LPA预处理可减轻所有细胞凋亡模型的DNA断裂。在喜树碱处理后1小时或照射后2小时使用LPA可使细胞免于凋亡。LPA抑制caspase-3/CPP32的活化，并使其活性减弱。百日咳毒素阻断LPA(1)受体和抑制上皮生长因子受体酪氨酸激酶可显著减弱其保护作用。在辐照小鼠中，口服LPA显著减少了隐窝中凋亡小体的数量。结论：(1)LPA对4种不同机制诱导的IEC-6细胞凋亡具有抑制和恢复作用。(2)这种抗凋亡活性是通过LPA介导的(1)。和LPA(2)受体通过抑制caspase-3/CPP32的激活。(3) LPA对辐射诱导的肠细胞凋亡具有保护作用。这项研究表明，在接受癌症治疗的患者中，饮食中的LPA可能在肠上皮中具有治疗上有用的抗凋亡能力。
Background & Aims: We have investigated whether the phospholipid growth factor lysophosphatidic acid (LPA) could prevent intestinal epithelial cells-6 (IEC-6) from apoptosis elicited by 4 different mechanisms. The antiapoptotic effect of LPA was also tested in a mouse model of radiation-induced apoptosis. Methods: Apoptosis was elicited by serum withdrawal, exposure to camptothecin, T-irradiation, or rat tumor necrosis factor alpha and evaluated by DNA fragmentation enzyme-linked immunosorbent assay (ELISA) and annexin V staining. Caspase-3/CPP32 activity and activation was measured by ELISA and Western blotting, respectively. Reverse-transcription polymerase chain reaction (RT-PCR) was applied to examine the expression of LPA-receptor transcripts. Mice were treated with 250 ILL of 1 mmol/L LPA and exposed to whole-body T-irradiation with a dose of 12 or 15 Gy and the number and localization of apoptotic bodies along the crypt were recorded. Results: LPA pretreatment reduced DNA fragmentation induced in all models of apoptosis. LPA rescued cells from apoptosis when applied up to I hour after camptothecin treatment or 2 hours after irradiation. LPA inhibited the activation of caspase-3/CPP32 and attenuated its activity. Blocking LPA(1) receptors by pertussis toxin and the inhibition of epithelial growth factor receptor tyrosine kinase significantly attenuated the protective effect. In irradiated mice, oral LPA significantly reduced the number of apoptotic bodies in the crypt. Conclusions: (1) LPA prevents and rescues IEC-6 from apoptosis elicited by 4 different mechanisms. (2) This antiapoptotic activity is mediated through LPA(1). and LPA(2) receptors through the inhibition of caspase-3/CPP32 activation. (3) LPA protects enterocytes against radiation-induced apoptosis. This study suggests that in patients undergoing cancer therapy, dietary LPA might have therapeutically useful antiapoptotic capacity in the intestinal epithelium.