Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells
Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells
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DOI：
10.1038/labinvest.3700267
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发表时间：
2005-05-01
影响因子：
5
通讯作者：
Pance, A
中科院分区：
文献类型：
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作者：
Bentrari, F;Arnould, L;Pance, A
激素受体的存在与乳腺癌患者的生存结局有关。我们实验室以前的结果在一系列人类乳腺肿瘤中建立了一氧化氮合酶II(NOSII)和一氧化氮(NO)与孕激素受体产生之间的相关性。此外，这与较低的肿瘤级别和较低的肿瘤细胞增殖率直接相关。为了更详细地检验这些结果，分析了孕酮(PG)和17β-雌二醇(E2)对人乳腺癌细胞株MCF-7中NOSII表达的影响。通过Northern印迹和启动子活性检测，我们发现混合细胞因子(肿瘤坏死因子-α、IL-β和干扰素-γ)在刺激6h后可诱导NOSII转录。在缺乏细胞因子的情况下，这两种激素都不会影响NOSII的表达。然而，PG而不是E2增强了细胞因子诱导的NOSII转录和NO的合成，主要是通过与伽玛-干扰素合作实现的。与单独使用细胞因子相比，在细胞因子处理中加入PG诱导的NO积聚显著增加细胞死亡，其主要原因是细胞凋亡。我们的发现有助于阐明类固醇激素在NOSII表达中的作用以及对细胞活性的影响，并可能为激素治疗和癌症治疗提供新的方法。
The presence of hormone receptors is related to survival outcome in breast cancer. Previous results from our laboratory established a correlation between the presence of nitric oxide synthase II (NOSII) and nitric oxide (NO) production with progesterone receptors in a series of human breast tumours. Furthermore, this was directly related to a lower tumour grade and a lower proliferation rate of the tumour cells. To examine these results in further detail, the effect of progesterone (Pg) and 17 beta-oestradiol (E2) on NOSII expression was analysed in the human breast cancer cell line MCF-7. By Northern blot and promoter activity, we show that a cytokine mix (TNF-alpha, IL-beta, and IFN-gamma) induces NOSII transcription after 6 h stimulation. In the absence of cytokines, neither hormone affects NOSII expression. However, Pg but not E2, enhances cytokine-induced NOSII transcription as well as NO synthesis, mainly by cooperation with gamma-interferon. The increase in NO accumulation in the media induced by addition of Pg to the cytokine treatment significantly increases cell death, mainly accounted for by apoptosis, as compared to the effect of cytokines alone. Our findings help clarify the role of steroid hormones in NOSII expression as well as the effect on cell viability and may suggest novel approaches towards hormonotherapy and the treatment of cancer.