Molecular Determinants for the Bioactivity of the Flavonoid Quercetin

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DESCRIPTION (provided by applicant): Flavonoids constitute a group of polyphenolic compounds primarily known for their anti-oxidant properties. Studies on flavonoids show their promising use for the prevention and treatment of a variety of cancer, inflammatory and heart diseases. Quercetin is a naturally occurring bioactive flavonoid ubiquitously available in fruits, vegetables and other plants. Several studies have shown the bioactivity of Quercetin against a variety of tumor cells and angiogenesis. However, several other studies have also indicated the carcinogenic potential of Quercetin. Moreover, Quercetin has been described as one of the principal molecules of some toxic plants. Therefore, the conditions under which Quercetin is bioactive as an anti-tumor agent or as a carcinogen are not well known. Understanding how Quercetin and other flavonoids function at the molecular level is of paramount importance to public health because it will help us establish the conditions under which specific bioactive flavonoid compounds may or may not be beneficial for therapeutic purposes. In this study, we propose to determine the mechanisms of Quercetin bioactivity under conditions where specific protein regulators of cell signaling have been ablated. Our specific aims are to examine: (1) what genes are expressed or inhibited by Quercetin; (2) how Quercetin modulates cell survival or cell death through cell signaling regulatory proteins. To address these aims, firstly, we will study the global and differential gene expression profiles of cells, which are intact or null for the p53 protein, by treating them with Quercetin. We will also examine the effect of Quercetin on the expression and function of cell cycle and apoptosis proteins regulated by p53. Secondly, we will analyze the DNA-damage response pathway through examination of the ATM/ATR proteins and downstream events. Thirdly, we will examine the levels and activities of other key cell cycle and apoptosis regulatory proteins after treatment with Quercetin. To examine the role of key proteins identified through the initial treatment experiments, we will use cells knocked out for the proteins or we will knock down the proteins by short interfering RNAs. The results will help us understand if treatment with Quercetin influences cell cycle, apoptosis, and DNA-damage regulatory proteins in cells. In future studies, we will utilize knowledge from these aims to evaluate the effect that Quercetin exerts in tumor cells in vivo.