Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling

Dharmalingam Subramaniam, Sivapriya Ponnurangam, Prabhu Ramamoorthy, David Standing, Richard J Battafarano, Shrikant Anant, Prateek Sharma

Research output: Contribution to journalArticle

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. Methodology/Principal Findings: 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. Conclusion/Significance: 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.

Original languageEnglish (US)
Article numbere30590
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 17 2012
Externally publishedYes

Fingerprint

esophageal neoplasms
Curcumin
curcumin
Cell death
Esophageal Neoplasms
cell death
Cell Death
Cells
Amyloid Precursor Protein Secretases
Chemical activation
MicroRNAs
microRNA
mechanism of action
neoplasm cells
Down-Regulation
apoptosis
Growth
cell lines
Apoptosis
Presenilin-1

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Subramaniam, D., Ponnurangam, S., Ramamoorthy, P., Standing, D., Battafarano, R. J., Anant, S., & Sharma, P. (2012). Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. PLoS One, 7(2), [e30590]. https://doi.org/10.1371/journal.pone.0030590

Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. / Subramaniam, Dharmalingam; Ponnurangam, Sivapriya; Ramamoorthy, Prabhu; Standing, David; Battafarano, Richard J; Anant, Shrikant; Sharma, Prateek.

In: PLoS One, Vol. 7, No. 2, e30590, 17.02.2012.

Research output: Contribution to journalArticle

Subramaniam, D, Ponnurangam, S, Ramamoorthy, P, Standing, D, Battafarano, RJ, Anant, S & Sharma, P 2012, 'Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling', PLoS One, vol. 7, no. 2, e30590. https://doi.org/10.1371/journal.pone.0030590
Subramaniam, Dharmalingam ; Ponnurangam, Sivapriya ; Ramamoorthy, Prabhu ; Standing, David ; Battafarano, Richard J ; Anant, Shrikant ; Sharma, Prateek. / Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. In: PLoS One. 2012 ; Vol. 7, No. 2.
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