Journal
CARCINOGENESIS
Volume 31, Issue 4, Pages 719-728Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgq016
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Funding
- American Cancer Society [CNE-111611]
- National Institutes of Health [R01CA108975, R03CA137755]
- University of Tennessee
- Center of Excellence in Livestock Diseases and Human Health
- Royal Golden Jubilee PhD Program [PHD/0245/2545]
- Office of the Higher Education Commission, Thailand
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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 beta (C/EBP beta) caused a significant increase of basal and capsaicin-induced NAG-1 promoter activity. We subsequently identified C/EBP beta 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/EBP beta to the NAG-1 promoter. Capsaicin treatment resulted in an increase of phosphorylated serine/threonine residues on C/EBP beta, and the immunoprecipitation study showed that capsaicin enhanced binding of C/EBP beta with glycogen synthase kinase 3 beta (GSK3 beta) and activating transcription factor 3 (ATF3). The phosphorylation and interaction of C/EBP beta with GSK3 beta and ATF3 are decreased by the inhibition of the GSK3 beta and Protein Kinase C pathways. Knockdown of C/EBP beta, GSK3 beta or ATF3 ameliorates NAG-1 expression induced by capsaicin treatment. These data indicate that C/EBP beta phosphorylation through GSK3 beta may mediate capsaicin-induced expression of NAG-1 and apoptosis through cooperation with ATF3 in human colorectal cancer cells.
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