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Patel, Snehal T.
Languages: English
Types: Doctoral thesis
Subjects: RC0254
The aim of this study was to investigate the role of the adipokine visfatin as a possible\ud molecular mediator between obesity and prostate cancer.\ud Visfatin, an adipokine that is elevated in obesity and has many proposed roles and has\ud been linked to a variety of cancers. No data pertaining to the role of visfatin in prostate\ud cancer existed and this was an area that this study looked to address. It is suggested\ud that obesity is a significant risk factor for prostate cancer; in particular, aggressive\ud disease and adipokines have been investigated as a link for this hypothesis.\ud This study presents novel data demonstrating the expression of visfatin in the LNCaP\ud and PC3 cell lines as well as in benign and cancerous prostate tissue at both mRNA\ud and protein level. Furthermore visfatin is shown to have functional roles in autoregulation\ud and promoting increased cell proliferation in PC3 cells and also showed\ud further effects with respect to cell migration across a wound. These data gave promise\ud to develop the study further and evaluate potential mechanisms of action including\ud common second messenger systems such as MAPK and also other oncologically\ud multifunctional molecules in the forms of MMP-2/-9. We then demonstrated that visfatin\ud up-regulated MAPK phosphorylation and MMP mRNA/protein expression and more\ud importantly MMP-2/-9 zymographic activity. This provided possible mechanisms by\ud which visfatin may mediate a role for obesity driven aggressive prostate cancer.\ud The study then looked to evaluate NMN (the byproduct of visfatin catalysed\ud biosynthetic activity), as well as the visfatin inhibitor FK866 which is being evaluated as\ud chemotherapeutic agent. Unsurprisingly NMN and FK866 had opposing actions on\ud proliferation and FK866 was naturally proapoptotic. NMN was able to rescue the effect\ud of FK866 on PC3 cell apoptosis. Prior studies have shown that NMN did not affect\ud oncogenes however NMN was found to significantly reduce BAX mRNA expression in\ud PC3 cells.\ud The findings are consistent with other studies linking visfatin with cancer states. These\ud novel data indicate roles for visfatin in prostate cancer and possible mechanisms linking\ud obesity and prostate cancer.

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