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NAD+ salvage by Nicotinamide phosphoribosyltransferase (Nampt) mediates lipogenesis, energy homeostasis, and survival in prostate cancer

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abstract
Traditionally, nicotinamide adenine dinucleotide (NAD+) is recognized as a redox cofactor which participates in numerous metabolic reactions. However, new evidence shows that many enzymes consume NAD+ as a substrate to regulate activities from posttranslational modifications to DNA repair and apoptosis. The rate-limiting step of NAD+ biosynthesis in the salvage pathway is catalyzed by Nicotinamide phosphoribosyltransferase (Nampt). In these studies, we focus on the role of Nampt in tumor biology. Specifically, we demonstrate that Nampt activity is required for de novo lipogenesis in multiple cancer cell lines. Inhibition of Nampt causes a reduction in ATP levels which correlates with phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC). Inhibition of the NAD+-dependent sirtuin deacetylases by Sirtinol treatment, or SIRT1/SIRT3 knockdown, phenocopied the effects of Nampt blockade on fatty acid synthesis thereby suggesting that Nampt maintains lipogenesis through sirtuin-dependent mechanisms. Additionally, we made the novel observation that Nampt inhibition causes endoplasmic reticulum (ER) stress in tumor cells and activates the Protein kinase R-like ER kinase (PERK) signaling arm of the unfolded protein response (UPR). In response to Nampt inhibition, PERK activity facilitates autophagy and survival in transformed cells. In human tumors, expression and tissue microarray analysis revealed that mRNA and protein levels of the potent NAD+ hydrolase CD38 are diminished in prostate cancer. CD38 protein levels were high in normal prostate cells and low in cancer prostate cancer cell lines, which correlated with high NAD+ levels in the tumorigenic cells. This indicates that high NAD+ levels may be advantageous to prostate tumors, and are achieved through loss of CD38. Our work also elucidated a role for extracellular Nampt (eNampt), in that prostate cancer cells can secrete their own eNampt, and this secretion is increased by androgen stimulation. Furthermore, eNampt treatment of tumor cells increased expression of fatty acid synthase (FASN) and cell proliferation through the oncogenic Phosphatidylinositol 3 kinase (PI3K) pathway, indicating that eNampt exerts signaling effects on prostate cancer cells. In all, our work provides insight into NAD+ biology in prostate cancer and elucidates how Nampt and eNampt are important regulators of prostate tumor cell metabolism, energy homeostasis, and survival.
subject
contributor
Bowlby, Sarah Chamberlain (author)
Kridel, Steven J (committee chair)
Wang, Yuh-Hwa (committee member)
Dubey, Purnima (committee member)
Chen, Yong Q (committee member)
Parks, Griffith D (committee member)
date
2012-06-12T08:35:39Z (accessioned)
2012 (issued)
degree
Cancer Biology (discipline)
10000-01-01 (liftdate)
embargo
forever (terms)
identifier
http://hdl.handle.net/10339/37247 (uri)
language
en (iso)
publisher
Wake Forest University
title
NAD+ salvage by Nicotinamide phosphoribosyltransferase (Nampt) mediates lipogenesis, energy homeostasis, and survival in prostate cancer
type
Dissertation

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