Induction of apoptotic cell death by putrescine
Induction of apoptotic cell death by putrescine
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DOI：
10.1016/j.biocel.2005.10.020
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Persson, L
中科院分区：
文献类型：
--
作者：
Takao, K;Rickhag, M;Persson, L
多胺是细胞生长和分化所必需的。鸟氨酸脱羧酶（ODC）是多胺生物合成的第一步催化酶，具有非常快的周转速度，并受多胺的强烈反馈控制。在本研究中，我们表明，代谢稳定的ODC在CHO细胞中的过度表达诱导大量的细胞死亡，除非细胞生长在ODC抑制剂α-二氟甲基鸟氨酸（DFMO）的存在下。另一方面，过表达野生型（不稳定）ODC的细胞不依赖于DFMO的存在来生长。细胞死亡的诱导与细胞腐胺水平的急剧增加相关。流式细胞术分析显示细胞周期动力学紊乱，大量DNA含量低于G（1）的细胞聚集，这是凋亡的典型标志。细胞凋亡的另一个强有力的迹象是发现当从生长培养基中省略DFMO时，诱导了细胞凋亡过程中的关键酶之一半胱天冬酶-3。此外，半胱天冬酶活性的抑制显著减少了细胞向sub-G（1）组分的募集。总之，如果腐胺水平过高，多胺稳态失调可能会对细胞增殖产生负面影响，并最终导致细胞凋亡死亡。(c)2005爱思唯尔有限公司保留所有权利。
The polyamines are essential for cellular growth and differentiation. Ornithine decarboxylase (ODC), which catalyses the first step in the biosynthesis of the polyamines, has a very fast turnover and is Subject to a strong feedback control by the polyamines. In the present study, we show that overexpression of a metabolically stable ODC in CHO cells induced a massive cell death unless the cells were grown in the presence of the ODC inhibitor alpha-difluoromethylornithine (DFMO). Cells overexpressing wild-type (unstable) ODC, on the other hand, were not dependent oil the presence of DFMO for their growth. The induction of cell death was correlated with a dramatic increase in cellular putrescine levels. Analysis using flow cytometry revealed perturbed cell cycle kinetics, with a large accumulation of cells with sub-G(1) amounts of DNA, which is a typical sign of apoptosis. Another strong indication of apoptosis was the finding that one of the key enzymes in the apoptotic process, caspase-3, was induced when DFMO was omitted from the growth medium. Furthermore, inhibition of the caspase activity significantly reduced the recruitment of cells to the sub-G(1) fraction. In conclusion, deregulation of polyamine homeostasis may negatively affect cell proliferation and eventually lead to cell death by apoptosis if putrescine levels become too high. (c) 2005 Elsevier Ltd. All rights reserved.