Exploring the anticarcinogenic properties of apple procyanidins in the oesophagus:effects on the MAPK signalling pathways

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Epidemiological evidence suggests a protective effect of diets rich in fruits and vegetables against oesophageal adenocarcinoma (OA), an increasingly important disease in the UK. Such diets are rich in proanthocyanidins and procyanidins, polymeric flavan-3-ols that have been demonstrated to have anticancer effects against various human in vitro and animal in vivo models, where the observed antiproliferative effects include the induction of cell cycle arrest and/or apoptosis. Recent studies with various cancer cells and our own preliminary research with OA cells have indicated that modulation of the activity of one or more of the mitogen-activated protein kinase (MAPK) signalling pathways may be the mechanism by which proanthocyanidins exert their biological effects. We will explore this mechanism by identifying specific MAPK pathway components whose expression and/or phosphorylation (activity) status is altered by exposure to a well-characterised procyanidin from apples. We will elucidate the relative importance of the molecular changes in the induction of cell cycle arrest and apoptosis. Using specific kinase inhibitors to inhibit pathway activities, and siRNAs to knock down particular pathway genes, we will determine their downstream effects and thus deepen our understanding of how flavonoids from fruits impact upon OA.

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