NSAID-activated gene-1 as a molecular target for capsaicin-induced apoptosis through a novel molecular mechanism involving GSK3beta, C/EBPbeta and ATF3.
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/EBPbeta) caused a significant increase of basal and capsaicin-induced NAG-1 promoter activity. We subsequently identified C/EBPbeta 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/EBPbeta to the NAG-1 promoter. Capsaicin treatment resulted in an increase of phosphorylated serine/threonine residues on C/EBPbeta, and the immunoprecipitation study showed that capsaicin enhanced binding of C/EBPbeta with glycogen synthase kinase 3beta (GSK3beta) and activating transcription factor 3 (ATF3). The phosphorylation and interaction of C/EBPbeta with GSK3beta and ATF3 are decreased by the inhibition of the GSK3beta and Protein Kinase C pathways. Knockdown of C/EBPbeta, GSK3beta or ATF3 ameliorates NAG-1 expression induced by capsaicin treatment. These data indicate that C/EBPbeta phosphorylation through GSK3beta may mediate capsaicin-induced expression of NAG-1 and apoptosis through cooperation with ATF3 in human colorectal cancer cells.
Mesh Terms:
Activating Transcription Factor 3, Apoptosis, CCAAT-Enhancer-Binding Protein-beta, Capsaicin, Colorectal Neoplasms, Glycogen Synthase Kinase 3, Growth Differentiation Factor 15, HCT116 Cells, HT29 Cells, Humans, Phosphorylation, Promoter Regions, Genetic, Protein Kinase C, Receptors, Retinoic Acid, Signal Transduction
Activating Transcription Factor 3, Apoptosis, CCAAT-Enhancer-Binding Protein-beta, Capsaicin, Colorectal Neoplasms, Glycogen Synthase Kinase 3, Growth Differentiation Factor 15, HCT116 Cells, HT29 Cells, Humans, Phosphorylation, Promoter Regions, Genetic, Protein Kinase C, Receptors, Retinoic Acid, Signal Transduction
Carcinogenesis
Date: Apr. 01, 2010
PubMed ID: 20110283
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