Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling.
Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling.
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DOI：
10.1371/journal.pone.0030590
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sharma P
中科院分区：
文献类型：
--
作者：
Subramaniam D;Ponnurangam S;Ramamoorthy P;Standing D;Battafarano RJ;Anant S;Sharma P
姜黄素抑制食管癌细胞系的生长;然而，其作用机制尚不清楚。越来越清楚的是，Notch信号传导的异常激活与食管癌的发展有关。在这里，我们已经确定姜黄素通过Notch信号通路介导的机制抑制食管癌生长。在这项研究中，我们表明，姜黄素治疗导致食管癌细胞系的增殖和集落形成的剂量和时间依赖性抑制。此外，姜黄素治疗诱导凋亡通过caspase 3激活，证实了Bax的比例增加Bcl 2。细胞周期分析表明，姜黄素处理诱导细胞死亡和下调细胞周期蛋白D1水平。姜黄素治疗还导致食管球的数量和大小减少。此外，姜黄素处理导致Notch-1活化、Jagged-1及其下游靶点Hes-1的表达减少。确定Notch-1活化的这种减少是由于γ-分泌酶复合物蛋白的关键组分如早老素1和Nicastrin的下调。已知的γ-分泌酶抑制剂DAPT和姜黄素的组合进一步降低食管癌细胞的增殖并诱导凋亡。最后，姜黄素治疗下调Notch-1特异性microRNAs miR-21和miR-34 a的表达，并上调肿瘤抑制因子let-7a miRNA。姜黄素是食管癌生长的有效抑制剂，靶向Notch-1激活γ-分泌酶复合物蛋白。这些数据表明，Notch信号传导抑制是姜黄素在食管癌治疗干预期间的一种新的作用机制。
Curcumin inhibits the growth of esophageal cancer cell lines; however, the mechanism of action is not well understood. It is becoming increasingly clear that aberrant activation of Notch signaling has been associated with the development of esophageal cancer. Here, we have determined that curcumin inhibits esophageal cancer growth via a mechanism mediated through the Notch signaling pathway. In this study, we show that curcumin treatment resulted in a dose and time dependent inhibition of proliferation and colony formation in esophageal cancer cell lines. Furthermore, curcumin treatment induced apoptosis through caspase 3 activation, confirmed by an increase in the ratio of Bax to Bcl2. Cell cycle analysis demonstrated that curcumin treatment induced cell death and down regulated cyclin D1 levels. Curcumin treatment also resulted in reduced number and size of esophagospheres. Furthermore, curcumin treatment led to reduced Notch-1 activation, expression of Jagged-1 and its downstream target Hes-1. This reduction in Notch-1 activation was determined to be due to the down-regulation of critical components of the γ-secretase complex proteins such as Presenilin 1 and Nicastrin. The combination of a known γ-secretase inhibitor DAPT and curcumin further decreased proliferation and induced apoptosis in esophageal cancer cells. Finally, curcumin treatment down-regulate the expressions of Notch-1 specific microRNAs miR-21 and miR-34a, and upregulated tumor suppressor let-7a miRNA. Curcumin is a potent inhibitor of esophageal cancer growth that targets the Notch-1 activating γ-secretase complex proteins. These data suggest that Notch signaling inhibition is a novel mechanism of action for curcumin during therapeutic intervention in esophageal cancers.
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