Xanthohumol decreases Notch1 expression and cell growth by cell cycle arrest and induction of apoptosis in epithelial ovarian cancer cell lines
Xanthohumol decreases Notch1 expression and cell growth by cell cycle arrest and induction of apoptosis in epithelial ovarian cancer cell lines
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DOI：
10.1016/j.ygyno.2011.04.027
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发表时间：
2011-08-01
影响因子：
4.7
通讯作者：
Rose, Stephen L.
中科院分区：
文献类型：
--
作者：
Drenzek, Jessica G.;Seiler, Nicole L.;Rose, Stephen L.
Objective. Notch 1信号在卵巢癌中是活跃的，是卵巢癌新疗法的一个有前途的途径。我们以前检测到Notch 1在卵巢肿瘤中的高表达。黄腐酚已显示出抑制癌细胞生长和侵袭，包括卡波西肉瘤，其也高度表达Notch 1。我们假设Notch 1信号通路被黄腐酚靶向，导致卵巢癌细胞生长减少。利用了SKOV 3和OVCAR 3细胞。用黄腐酚处理后进行MTT生长测定。进行定量RT-PCR和Western印迹分析以评估Notch 1下调。进行荧光素酶报告基因测定以评估Notch 1的功能下调。流式细胞仪检测细胞周期。黄腐酚处理后，Notch 1基因的转录和蛋白表达均受到显著抑制。此外，黄腐酚增加了Hes 6的转录，降低了Hes 1的转录，这是Notch 1的已知下游靶点。这些观察结果与细胞周期抑制有关，如p21表达增加所证实，S和G2/M细胞周期阻滞由磷酸化cdc 2增加证实。此外，凋亡标志物、裂解的caspase-3和裂解的PARP的增加被抑制。黄腐酚是卵巢癌细胞生长的有效抑制剂，我们的研究结果表明，黄腐酚可能会影响Notch 1通路。这些发现表明，黄腐酚可能是有用的作为卵巢癌的治疗剂。(C)2011 Elsevier Inc. All rights reserved.
Objective. Notch1 signaling is active in ovarian cancer and is a promising pathway for new therapies in ovarian cancer. We have previously detected high Notch1 expression in ovarian tumors. Xanthohumol has been shown to inhibit cancer cell growth and invasion, including Kaposi's sarcoma, which also highly expresses Notch1. We hypothesized that the Notch1 signaling pathway is targeted by xanthohumol leading to decreased ovarian cancer cell growth.Methods. SKOV3 and OVCAR3 cells were utilized. MTT growth assays were conducted following treatment with xanthohumol. Quantitative RT-PCR and Western blot analyses were conducted to assess Notch1 down-regulation. Luciferase reporter assays were performed to assess functional down-regulation of Notch1. Cell cycle analysis was performed by flow cytometry.Results. Significant growth inhibition and down-regulation of Notch1 transcription and protein expression were found following xanthohumol treatment. In addition, xanthohumol increased Hes6 transcription and decreased Hes1 transcription, known downstream targets of Notch 1. These observations were associated with cell cycle inhibition as demonstrated by an increase in p21 expression and S and G2/M cell cycle arrest confirmed by an increase in phosphorylated cdc2. Furthermore, an increase in the apoptotic markers, cleaved caspase-3 and cleaved PARP were observed.Conclusion. Xanthohumol was a potent inhibitor of ovarian cancer cell growth, and our results suggest that xanthohumol may be influencing the Notch1 pathway. These findings suggest that xanthohumol could be useful as a therapeutic agent in ovarian cancer. (C) 2011 Elsevier Inc. All rights reserved.