Estradiol control of ornithine decarboxylase mRNA, enzyme activity, and polyamine levels in MCF-7 breast cancer cells: therapeutic implications
Estradiol control of ornithine decarboxylase mRNA, enzyme activity, and polyamine levels in MCF-7 breast cancer cells: therapeutic implications
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雌二醇对 MCF-7 乳腺癌细胞中鸟氨酸脱羧酶 mRNA、酶活性和多胺水平的控制：治疗意义
DOI：
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发表时间：
2004
影响因子：
3.8
通讯作者：
T. Thomas
中科院分区：
文献类型：
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作者：
T. Thomas;T. Thomas
以前的研究表明，天然多胺-腐胺，亚精胺和精胺-在乳腺癌中雌激素的作用机制中起着关键作用。鸟氨酸脱羧酶（ODC）是多胺生物合成途径中的第一个酶。为了研究雌激素对乳腺癌中多胺生物合成的调节，我们测定了G1期同步化MCF-7细胞中ODC mRNA、ODC活性和多胺水平。ODC的mRNA和活性增加4倍以上的细胞在G1期之间的8至16小时后加入雌二醇。多胺水平在添加雌二醇后8 h急剧升高，12 h下降。我们进一步研究了腐胺或亚精胺的合成同系物是否可以取代天然多胺支持MCF-7细胞生长。用1 mM二氟甲基鸟氨酸（DFMO）（一种ODC抑制剂）处理MCF-7细胞，在48 h内，腐胺、亚精胺和精胺水平分别抑制了74%、78%和10%。用DFMO处理48小时的细胞补充腐胺或其同系物或亚精胺或其同系物。二氨基丙烷，二氨基丁烷（腐胺），和二氨基戊烷能够完全或部分逆转DFMO的生长抑制作用，而二氨基乙烷没有显着的效果。在一系列三胺中，H2 N（CH 2）nNH（CH 2）3 NH 2（其中n = 2至8;对于亚精胺，缩写为APn n n = 4，或AP 4），亚精胺在逆转DFMO的作用方面最有效，而具有较短或较长亚甲基桥接区域的化合物效果较差。AP 8不能逆转DFMO的生长抑制作用。在10 µM浓度下，通过[3 H]-胸苷掺入测定，AP 8还可抑制66%的DNA合成。这些数据表明，MCF-7细胞的生长对多胺有很强的需求，雌二醇通过诱导ODC mRNA水平刺激多胺级联反应。我们的研究结果还表明，多胺同系物，如AP 8可能是潜在的有用的乳腺癌治疗。
Previous studies have shown that natural polyamines - putrescine, spermidine, and spermine - play a key role in the mechanism of action of estrogens in breast cancer. Ornithine decarboxylase (ODC) is the first enzyme of the polyamine biosynthetic pathway. To examine estrogenic regulation of polyamine biosynthesis in breast cancer, we measured ODC mRNA, ODC activity, and polyamine levels in G1 synchronized MCF-7 cells. ODC mRNA and activity increased four-fold over that of cells in G1 phase between 8 to 16 h after the addition of estradiol. Polyamine levels showed a sharp increase by 8 h after the addition of estradiol and decreased by 12 h. We further examined whether synthetic homologs of putrescine or spermidine could replace natural polyamines in supporting MCF-7 cell growth. Treatment of MCF-7 cells with 1 mM difluoromethylornithine (DFMO), an inhibitor of ODC, suppressed putrescine, spermidine, and spermine levels by 74, 78, and 10%, respectively, within 48 h. Cells treated with DFMO for 48 h were supplemented with either putrescine or its homologs or spermidine or its homologs. Diaminopropane, diaminobutane (putrescine), and diaminopentane were capable of fully or partially reversing the growth inhibitory effects of DFMO, whereas diaminoethane had no significant effect. Among a series of triamines, H2N(CH2)nNH(CH2)3NH2 (where n = 2 to 8; abbreviated as APn n = 4 for spermidine, or AP4), spermidine was most effective in reversing the effects of DFMO, whereas compounds with shorter or longer methylene bridging regions were less effective. AP8 was ineffective in reversing the growth inhibitory effects of DFMO. At 10 µM concentration, AP8 also inhibited DNA synthesis by 66%, as measured by [3H]-thymidine incorporation. These data show that MCF-7 cells have a strong requirement for polyamines for their growth and that estradiol stimulates the polyamine cascade by inducing the ODC mRNA level. Our results also suggest that polyamine homologs such as AP8 might be potentially useful in breast cancer therapy.
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