Curcumin Induces Cell Death in Esophageal Cancer Cells through Modulating Notch Signaling

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.

The pathological significance of Notch1 in oral squamous cell carcinoma

“…In these reports, MMPs, the nuclear factor-kB pathway and micro-RNAs were reported to be associated with increases in invasive phenotypes. 46,47 Our data support these previous findings and we conclude that Notch1 has a role in a certain type of OSCC invasion. However, we need further investigation to determine what mechanisms underlie the invasiveness of OSCC cells because Notch signaling shows cross-talk with many other pathways and regulates the properties of these pathways based on complicated mechanisms.…”

Curcumin and Silibinin Inhibit Telomerase Expression in T47D Human Breast Cancer Cells

“…In other words, it seems that the effect of curcumin on T47D breast cancer cell line is time-and dose-dependent. Other studies shows that curcumin has inhibitory effect in the cells growth on the various types of cancer cell lines usually with a timedependent manner (Syng-Ai et al, 2004;Chakravarti et al, 2010;Watson et al, 2010;Subramaniam et al, 2012). Curcumin exerts its anticancer effect on different cellular factors (Sa and Das, 2008;Wilken, 2011).…”

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

“…Curcumin was found to induce miR-203 transcription in bladder cancer cells that leads to downregulation of miR-203 target genes Akt2 and Src, culminating in decreased cell proliferation and increased apoptosis (Saini et al, 2011). Upregulation of the tumor suppressor let-7a miRNA is associated with curcumin-induced apoptosis in esophageal cancer cells (Subramaniam et al, 2012). Our present data revealed that curcumin treatment resulted in a dose-dependent and significant elevation of miR-9 expression in SKOV3 ovarian cancer cells, compared to untreated control cells.…”