Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de Mexico, Mexico D.F. 04510, Mexico.
Steroids. 2013 Jul;78(7):717-25. doi: 10.1016/j.steroids.2013.03.003. Epub 2013 Apr 10.
We examined the ability of ICI 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or ICI at 08:00 h on the day of proestrus or at 00:00 h on the day of estrus and sacrificed at 13:00 h of metaestrus. Estradiol (E₂) and progesterone (P₄) plasma levels were measured by radioimmunoassay. Both ICI treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that ICI treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of ICI at 08:00 h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas ICI treatment at 00:00 h on estrus day had no effect on these parameters. The overall results indicate that ICI may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized + E₂ animal model.
我们研究了 ICI 182,780（ICI）通过蛋白激酶 b/AKT 通路阻断动情周期大鼠子宫细胞增殖的能力。正常动情周期的完整大鼠在动情前期的 08:00 时或发情期的 00:00 时接受皮下（s.c.）注射载体或 ICI，并在动情后期的 13:00 时处死。通过放射免疫测定法测量雌二醇（E₂）和孕酮（P₄）的血浆水平。与载体处理的动物相比，ICI 处理均导致子宫雌激素受体 α（ERα）含量显著降低（p<0.01），对子宫孕激素受体（PR）蛋白表达无影响，并导致细胞周期蛋白 D1 在腔上皮和腺上皮的核内明显定位。此外，我们检测到 ICI 处理诱导糖原合酶激酶（Gsk3-β）Ser 9 磷酸化，这与细胞周期蛋白 D1 的核内定位相关。然而，在两种不同的给药时间方案之间观察到一些差异。我们观察到在动情前期的 08:00 时给予 ICI 导致腔上皮细胞增殖抑制 15%，子宫湿重减少 21%，并导致 Akt 在 Ser 473 的磷酸化减少，而在发情期的 00:00 时给予 ICI 对这些参数没有影响。总体结果表明，ICI 可能通过依赖于动情周期期间的给药期激活 Akt 通路，对子宫细胞增殖产生激动剂和拮抗剂作用，并表明在动情周期的生理条件下细胞增殖的机制比在卵巢切除+E₂动物模型中更为复杂。
