title: Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America. dsubramaniam@kumc.edu
authors.forename: Dharmalingam
authors.initials: D
authors.lastname: Subramaniam
authors.forename: Sivapriya
authors.initials: S
authors.lastname: Ponnurangam
authors.forename: Prabhu
authors.initials: P
authors.lastname: Ramamoorthy
authors.forename: David
authors.initials: D
authors.lastname: Standing
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Battafarano
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: Prateek
authors.initials: P
authors.lastname: Sharma
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use*; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008954:Models, Biological; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D004151:Dipeptides; D035683:MicroRNAs; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D003474:Curcumin