Prostate Cancer Cell Growth: Stimulatory Role of Neurotensin and Mechanism of Inhibition by Flavonoids as Related to Protein Kinase C
Annual rept. 1 Jan 2007-31 Dec 2008
MASSACHUSETTS UNIV MEDICAL SCHOOL WORCESTER
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The purpose is to define the relationship between neurotensin NT and protein kinases and to investigate the mechanism by which flavonoids FLAV inhibit NT growth signaling in PC3 cells. The long-range scope is to determine the significance of NT in the negative effects of high fat intake on PC incidence and the positive effects of diets containing FLAV. Our results show that NT-induced growth signaling involves activation of PKC, that arachidonic acid metabolism and EGF receptor activation participate in the NT signaling process, that cell metabolism and ATP levels can influence NT receptor function, and that activated PKC most notably PKC alpha and beta can feed back to regulate the ability of NT receptor to bind NT and to initiate signaling. FLAV was found to exert differential effects on PKC isotype activation and downregulation. In addition, FLAV was shown to inhibit protein tyrosine kinase activity in PC3 cells and evidence supports the notion that this can input to regulate NT receptor function. NT receptor was shown to localize in caveolae and to be displaced when activated by NT. FLAV appeared to influence this response to NT. These findings have implications regarding mechanisms that regulate NT receptor function and the design of agents to block NT-induced growth signaling in PC.
- Medicine and Medical Research