Apoptotic signaling in polyamine analogue-treated SK-MEL-28 human melanoma cells.
Apoptotic signaling in polyamine analogue-treated SK-MEL-28 human melanoma cells.
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发表时间：
2001-09
期刊：
影响因子：
11.2
通讯作者：
Ying Chen;D. Kramer;P. Diegelman;S. Vujcic;C. Porter
中科院分区：
文献类型：
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作者：
Ying Chen;D. Kramer;P. Diegelman;S. Vujcic;C. Porter
N（1），N（11）-二乙基去甲精胺（DENSPM）是一种多胺类似物，作为实验性抗癌药物具有临床意义，并能引起某些细胞类型的凋亡反应。在这里，我们的特点多胺的影响和细胞凋亡信号的事件开始治疗SK-MEL-28人黑色素瘤与10 μ M DENSPM。多胺分解代谢酶亚精胺/精胺N（1）-乙酰转移酶（SSAT）的诱导作用最大，多胺池在16 h时耗尽，而早期凋亡在36 h时首次出现。在16和36小时之间寻找与凋亡信号相关的中间事件。线粒体跨膜电位（Δ Psi（m））在24 h开始丧失，随后在30 h细胞色素c释放到胞质溶胶中。线粒体完整性的丧失伴随着caspase-3活化和聚（ADP-核糖）聚合酶消化30至36 h。半胱天冬酶抑制剂Z-Asp-2，6-二氯苯甲酰氧基甲基酮使细胞对类似物诱导的半胱天冬酶-3活化具有抗性，并以剂量依赖性方式减少凋亡反应。由于多胺生物合成抑制剂实现的多胺减少抑制生长，但不引起细胞凋亡，我们寻找替代多胺相关的事件，专注于诱导SSAT。三个DENSPM类似物，差异诱导SSAT活性，但同样耗尽多胺池揭示了酶诱导和细胞色素c释放，半胱天冬酶激活和细胞凋亡之间的密切相关性。多胺氧化酶（一种氧化SSAT产生的乙酰化多胺并释放有毒副产物如H（2）O（2）和醛类的酶）的剂量依赖性抑制可阻止细胞色素c释放、半胱天冬酶激活和细胞凋亡。综上所述，研究结果表明，DENSPM诱导的细胞凋亡至少部分是通过大量诱导SSAT和相关的氧化事件启动的，随后由线粒体凋亡信号通路介导，如细胞色素c释放和半胱天冬酶激活所示。
N(1),N(11)-Diethylnorspermine (DENSPM) is a polyamine analogue with clinicalrelevance as an experimental anticancer agent and the ability to elicit a profound apoptotic response in certain cell types. Here, we characterize the polyamine effects and apoptotic signaling events initiated by treatment of SK-MEL-28 human melanoma with 10 microM DENSPM. Maximal induction of the polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) and polyamine pool depletion were seen by 16 h, whereas early apoptosis was first apparent at 36 h. Intermediate events related to apoptotic signaling were sought between 16 and 36 h. A loss of mitochondrial transmembrane potential (Deltapsi(m)) beginning at 24 h was followed by the release of cytochrome c into the cytosol at 30 h. Loss of mitochondrial integrity was accompanied by caspase-3 activation and poly(ADP-ribose) polymerase digestion from 30 to 36 h. The caspase inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone rendered cells resistant to analogue-induced caspase-3 activation and reduced the apoptotic response in a dose-dependent manner. Because polyamine reduction achieved by inhibitors of polyamine biosynthesis inhibited growth but did not cause apoptosis, we looked for alternative polyamine-related events, focusing on induction of SSAT. Three DENSPM analogues that differentially induced SSAT activity but similarly depleted polyamine pools revealed a close correlation between enzyme induction and cytochrome c release, caspase activation, and apoptosis. Dose-dependent inhibition of polyamine oxidase, an enzyme that oxidizes acetylated polyamines generated by SSAT and releases toxic by-products such as H(2)O(2) and aldehydes, prevented cytochrome c release, caspase activation, and apoptosis. Taken together, the findings indicate that DENSPM-induced apoptosis is at least partially initiated via massive induction of SSAT and related oxidative events and subsequently mediated by the mitochondrial apoptotic signaling pathway as indicated by cytochrome c release and caspase activation.