Enhancement of hypoxia-induced apoptosis of human breast cancer cells via STAT5b by momilactone B
Enhancement of hypoxia-induced apoptosis of human breast cancer cells via STAT5b by momilactone B
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DOI：
10.3892/ijo_00000030
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发表时间：
2008-09-01
影响因子：
5.2
通讯作者：
Yang, Young Mok
中科院分区：
文献类型：
--
作者：
Joung, Youn-Hee;Lim, Eun-Joung;Yang, Young Mok
我们之前已经证明，缺氧会通过乳腺癌细胞中的 Jak2/STAT5b 通路激活细胞周期蛋白 D I 启动子。大多数实体瘤含有缺氧成分和细胞周期蛋白 D1 的过度表达。本研究的目的是探讨莫米内酯B对乳腺癌细胞发挥抑制作用的分子机制。从韩国稻壳中提取的 Momilactone B 可抑制缺氧引起的人类乳腺癌细胞中磷酸 STAT5、STAT5b、细胞周期蛋白 D1 和 cdk4 蛋白水平的增加。 siRNA 实验抑制 STAT5b 表达，导致细胞周期蛋白 D1 减少。研究了缺氧条件（2% O-2）下乳腺癌细胞中莫米内酯 B 对细胞生长和凋亡相关基因表达的影响。在缺氧条件下，经莫米内酯 B 处理的细胞中，Bax 和 p21 表达上调，而 ppRb 和 bcl-2 表达下调。然而，p53蛋白水平没有变化。流式细胞术和Annexin-FITC染色显示，与未处理的缺氧细胞相比，用莫米内酯B处理的缺氧细胞中凋亡细胞的数量增加。此外，在缺氧条件下用莫米内酯B处理后，半胱天冬酶活性增加。这些结果表明，momilactone B 抑制乳腺癌细胞的生长，调节细胞凋亡相关基因的表达，并通过 STAT5b 和 caspase-3 依赖性途径诱导细胞凋亡。我们认为，momilactone B 通过 STAT5b 加速缺氧诱导的人乳腺癌细胞凋亡，可能是一种有效的乳腺癌化学预防或治疗剂。
We have shown previously that hypoxia activates the cyclin D I promoter via the Jak2/STAT5b pathway in breast cancer cells. Most solid tumors contain hypoxic components and overexpression of cyclin D1. The purpose of the present study was to investigate the molecular mechanism by which momilactone B exerts its inhibitory effects on breast cancer cells. Momilactone B, extracted from Korean rice hulls, suppressed hypoxia-induced increases in phospho-STAT5, STAT5b, cyclin D1, and cdk4 protein levels in human breast cancer cells. STAT5b expression was inhibited by siRNA experiments leading to decreased cyclin D1. The effects of momilactone B on cell growth and apoptosis-related gene expression were investigated in breast cancer cells under hypoxic conditions (2% O-2). Bax and p21 expression was found to be up-regulated, whereas ppRb and bcl-2 were down-regulated in momilactone B-treated cells under hypoxic, conditions. However, the p53 protein level did not change. Flow cytometry with Annexin-FITC staining showed that the number of apoptotic cells increased in hypoxic cells treated with momilactone B compared with untreated hypoxic cells. Furthermore., caspase activity increased upon treatment with momilactone B under hypoxic conditions. These results indicate that momilactone B inhibits the growth of breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through STAT5b and a caspase-3 dependent pathway. We suggest that momilactone B accelerates hypoxia-induced apoptosis of human breast cancer cells through STAT5b, and may represent an effective chemopreventive or therapeutic agent against breast cancer.