Procyanidin induces apoptosis of esophageal adenocarcinoma cells via JNK activation of c-Jun.
Procyanidins are polymeric flavanols found in fruits and vegetables and have shown anticarcinogenic/chemopreventive properties. We previously showed that oligomeric procyanidin extracted from apples induced cell cycle arrest and apoptosis in esophageal adenocarcinoma (OA) cells. To understand the mechanism of action, we determined transcriptomic changes induced by procyanidin in OA cells. Pathway analysis implicated mitogen-activated protein kinase signaling pathways in eliciting these responses. Procyanidin induced the activation of JNK and p38 and the phosphorylation and expression of c-Jun. Inhibition of JNK but not p38 kinase activity prevented the procyanidin-induced phosphorylation and expression of c-Jun. Knockdown of the expression of JNK1, JNK2, or JUN diminished procyanidin-induced effects on cell proliferation and apoptosis. c-Jun is a component of the transcription factor AP-1 and AP-1 binding sites are overrepresented in the promoters of procyanidin-induced genes. This indicates that JNK activation of c-Jun by procyanidin leads to the induction of apoptosis of OA cells and suggests a role for a c-Jun-mediated transcriptional program. These data provide a mechanistic understanding of how procyanidin specifically targets a distinct pathway involved in the induction of apoptosis in OA cells and will inform future studies investigating its use as a chemopreventive/therapeutic agent.
a Institute of Food Research , Norwich , UK.
Carol A
CA
Connor
Michiel
M
Adriaens
Roberto
R
Pierini
Ian T
IT
Johnson
Nigel J
NJ
Belshaw
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D044946:Biflavonoids / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D044945:Proanthocyanidins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
D044946:Biflavonoids; D044945:Proanthocyanidins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C017674:procyanidin; D002392:Catechin; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7