Journal Article

NSAID-activated gene-1 as a molecular target for capsaicin-induced apoptosis through a novel molecular mechanism involving GSK3β, C/EBPβ and ATF3

Seong-Ho Lee, Chutwadee Krisanapun and Seung Joon Baek

in Carcinogenesis

Volume 31, issue 4, pages 719-728
Published in print April 2010 | ISSN: 0143-3334
Published online January 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq016
NSAID-activated gene-1 as a molecular target for capsaicin-induced apoptosis through a novel molecular mechanism involving GSK3β, C/EBPβ and ATF3

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Capsaicin, a natural product of the Capsicum species of red peppers, is known to induce apoptosis and suppress growth. Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and antitumorigenic property in colorectal and lung cancer. Our data demonstrate that capsaicin leads to induction of apoptosis and up-regulates NAG-1 gene expression at the transcriptional level. Overexpression of CCAAT/enhancer binding protein β (C/EBPβ) caused a significant increase of basal and capsaicin-induced NAG-1 promoter activity. We subsequently identified C/EBPβ binding sites in the NAG-1 promoter responsible for capsaicin-induced NAG-1 transactivation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed binding of C/EBPβ to the NAG-1 promoter. Capsaicin treatment resulted in an increase of phosphorylated serine/threonine residues on C/EBPβ, and the immunoprecipitation study showed that capsaicin enhanced binding of C/EBPβ with glycogen synthase kinase 3β (GSK3β) and activating transcription factor 3 (ATF3). The phosphorylation and interaction of C/EBPβ with GSK3β and ATF3 are decreased by the inhibition of the GSK3β and Protein Kinase C pathways. Knockdown of C/EBPβ, GSK3β or ATF3 ameliorates NAG-1 expression induced by capsaicin treatment. These data indicate that C/EBPβ phosphorylation through GSK3β may mediate capsaicin-induced expression of NAG-1 and apoptosis through cooperation with ATF3 in human colorectal cancer cells.

Journal Article.  7306 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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