Curcumin Induces Cell Death in Esophageal Cancer Cells through Modulating Notch Signaling
Open Access
- 17 February 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (2), e30590
- https://doi.org/10.1371/journal.pone.0030590
Abstract
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.This publication has 53 references indexed in Scilit:
- Dysfunctional transforming growth factor-β signaling with constitutively active notch signaling in Barrett's esophageal adenocarcinomaCancer, 2011
- Gemcitabine Sensitivity Can Be Induced in Pancreatic Cancer Cells through Modulation of miR-200 and miR-21 Expression by Curcumin or Its Analogue CDFCancer Research, 2010
- Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cellsMedical Oncology, 2009
- E Series of Prostaglandin Receptor 2-Mediated Activation of Extracellular Signal-Regulated Kinase/Activator Protein-1 Signaling Is Required for the Mitogenic Action of Prostaglandin E2in Esophageal Squamous-Cell CarcinomaThe Journal of pharmacology and experimental therapeutics, 2008
- MicroRNA Expression Profiles Associated With Prognosis and Therapeutic Outcome in Colon AdenocarcinomaJAMA, 2008
- Trends in oesophageal cancer incidence and mortality in EuropeInternational Journal of Cancer, 2007
- γ‐secretase inhibitors exerts antitumor activity via down‐regulation of Notch and Nuclear factor kappa B in human tongue carcinoma cellsOral Diseases, 2007
- Curcumin-induced apoptosis of human colon cancer colo 205 cells through the production of ROS, Ca2+ and the activation of caspase-3.2007
- Notch signaling in gastrointestinal tract (review).International Journal of Oncology, 2007
- Notch signaling.Clinical Cancer Research, 2006