Prostate Cancer Cell Growth: Stimulatory Role of Neurotensin and Mechanism of Inhibition by Flavonoids as Related to Protein Kinase C

摘要

We investigated the mechanisms by which flavonoids (FLAV) alter neurotensin receptor (NTR) function in PC3 cells in order to shed light on the role of NT in the negative effects of fat intake on PC incidence and the positive effects of Asian diets. We found that NTR is subject to heterologous regulation by PKC. Conventional PKCs appear to exert negative effects, whereas novel PKCs exert positive effects. Our results suggest that FLAV modulate NTR by a number of mechanisms, one of which could be to alter the balance between conventional and novel PKCs. Other potential mechanisms supported by experiments reported here involve receptor tyrosine kinases, lipoxygenases and cellular metabolism. We also show here that NTR is localized to membrane caveolae, and that the agonist NT caused a decrease in the level of NTR in these signaling modules. Beta cyclodextrin, which disrupts caveolae by removing cholesterol from membranes, displaced NTR from caveolae and produced FLAV-like effects on NTR. Although FLAV did not displace NTR from caveolae, this suggested that FLAV might interact with membranes to induce similar conformational changes in NTR that alter its function. These findings have implications regarding mechanisms that regulate NTR function and the design of agents to block NT-induced growth signaling in PC.