Huber M, Poulin R
Laboratory of Molecular Endocrinology, Laval University Medical Research Centre, Ste. Foy, Quebec, Canada.
Mol Cell Endocrinol. 1996 Mar 25;117(2):211-8. doi: 10.1016/0303-7207(95)03749-7.
Mutual interactions between 17 beta-estradiol (E2) and insulin or insulin-like growth factor-I (IGF-1) in the regulation of ornithine decarboxylase (ODC) expression were examined in estrogen-responsive MCF-7 human breast cancer cells. Whereas E2 only retarded the rapid decay of ODC activity observed upon mitogen withdrawal, both insulin and IGF-1 led to a rapid (< 4 h), net increase in ODC activity that was mediated, at least in part, through their cognate receptors. E2 synergistically potentiated the induction of ODC by IGF-1, resulting in a 170-fold elevation of enzyme activity after 48 h, as compared with 23- and 70-fold increases caused by E2 and IGF-1 alone, respectively. Cooperativity was more pronounced at suboptimal peptide concentrations due to a decrease in the half-maximal concentration of insulin or IGF-1 required for ODC induction. Phorbol-12-myristate-13-acetate (PMA) also strongly induced ODC activity in a transient manner, and additively to the effect of IGF-1. IGF-1 and PMA additively increased ODC mRNA level, whereas E2 alone had no effect on ODC mRNA abundance. IGF-1 increased the half-life of ODC activity by 60%, whereas E2 or PMA alone had no significant effect on enzyme stability. On the other hand, the simultaneous addition of IGF-1 and either E2 or PMA cooperatively reduced ODC turnover, resulting in 3.5- and 2-fold increases, respectively, in the half-life of ODC activity. Thus, ODC expression in breast cancer cells is primarily regulated by tyrosine kinase- and protein kinase C-dependent pathways, whereas estrogens increase ODC activity through a novel type of synergistic interaction with growth factors that results in a decreased rate of enzyme turnover.
在雌激素反应性MCF-7人乳腺癌细胞中，研究了17β-雌二醇（E2）与胰岛素或胰岛素样生长因子-I（IGF-1）在调节鸟氨酸脱羧酶（ODC）表达中的相互作用。虽然E2仅延缓了有丝分裂原撤除后观察到的ODC活性的快速衰减，但胰岛素和IGF-1均导致ODC活性迅速（<4小时）净增加，这至少部分是通过它们的同源受体介导的。E2协同增强了IGF-1对ODC的诱导作用，48小时后酶活性升高了170倍，而单独的E2和IGF-1分别导致酶活性升高23倍和70倍。由于诱导ODC所需的胰岛素或IGF-1的半数最大浓度降低，在次优肽浓度下协同作用更为明显。佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA）也以瞬时方式强烈诱导ODC活性，并且与IGF-1的作用相加。IGF-1和PMA相加增加ODC mRNA水平，而单独的E2对ODC mRNA丰度没有影响。IGF-1使ODC活性的半衰期增加了60%，而单独的E2或PMA对酶稳定性没有显著影响。另一方面，同时添加IGF-1和E2或PMA协同降低ODC周转率，导致ODC活性半衰期分别增加3.5倍和2倍。因此，乳腺癌细胞中ODC的表达主要受酪氨酸激酶和蛋白激酶C依赖性途径调节，而雌激素通过与生长因子的新型协同相互作用增加ODC活性，导致酶周转率降低。
