Abstract
BackgroundCurcumin 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.Methodology/Principal FindingsIn 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.Conclusion/SignificanceCurcumin 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.
Highlights
Esophageal cancer is the eighth most common incident cancer in the world and sixth in cancer mortality [1]
Curcumin inhibits esophageal cancer cell growth We determined the effect of curcumin on esophageal cancer cell proliferation in a variety of cultured cell lines (TE-7, TE-10 and Eso-1)
Curcumin significantly suppressed the proliferation of esophageal cancer cell lines TE-7, TE-10 and Eso-1 in dose and time dependent manner
Summary
Esophageal cancer is the eighth most common incident cancer in the world and sixth in cancer mortality [1]. Despite the emergence of novel targeted agents and the use of various therapeutic combinations, no treatment options are available that are curative in patients with advanced cancer The magnitude of this problem mandates the need for novel therapeutic agents, the use of agents for chemoprevention. Recent studies have demonstrated that curcumin promotes apoptosis, increases chemosensitivity, and inhibits NF-kB in esophageal adenocarcinoma [6] [7]. MiR-21 is upregulated 12.57-fold in esophageal cancer [21] Another important miRNA is miR-34, which has been found to participate in the regulation of p53 and Notch pathways consistent with tumor suppressor activity [22]. A recent study demonstrated that there is a cross-talk between miRNA and Notch signaling pathways in tumor development and progression [23]. We have determined the effect of curcumin on esophageal cancer cells and mechanism mediated through Notch signaling pathway
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