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The Physiological Effects of CD38 in Prostate Cancer: A multifunctional NAD'ase capable of regulating cell metabolism, gene expression, and therapeutic response

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The Physiological Effects of CD38 in Prostate Cancer: A multifunctional NAD'ase capable of regulating cell metabolism, gene expression, and therapeutic response
Chmielewski, Jeffrey P
Deregulation of cellular metabolism is a critical step during oncogenesis. Tumor cells rely heavily on changes to cell metabolism to support increased macromolecule biosynthesis, sustain membrane biogenesis, and cell survival. Nicotinamide adenine dinucleotide (NAD+) is linked all aspects of cell metabolism though its ability to act as both an oxidizing and reducing agent for hydride transfer reactions. Proper regulation of NAD+ is also vital to cells as it also serves as a substrate for three classes of NAD+ dependent enzymes: cyclic ADP-ribose synthases, sirtuins, and poly (ADP)-ribose polymerases (PARPs). The cyclic (ADP)-ribose synthase, CD38, is the primary NAD’ase in cells and has historically been regarded as an important cell surface molecule in cells of hematopoietic lineage. The work presented herein is focused on the role of CD38 in regulating prostate cancer (PCa) cell metabolism and therapeutic response. Prostate specific silencing of CD38 is inversely correlated with prostate cancer progression and results in increased availability of NAD+. Increased NAD+ resulting from CD38 silencing contributes to changes in the metabolic potential of PCa cells by elevating glycolytic and mitochondrial capacity and increasing fatty acid and lipid synthesis. The presence of multiple CpG islands in the promoter of CD38 is the proposed mechanism of CD38 silencing in PCa. Accordingly, we demonstrate treatment with the demethylating agent azacytidine is sufficient to induce CD38 mRNA levels. Our data also demonstrates treatment with all-trans retinoic acid (ATRA) is a viable strategy to rescue expression of CD38 independent of changes in epigenetic regulation. Interestingly, modulation of NAD+ levels by CD38 results in differential expression to more than 75% of the transcriptome generating a gene expression pattern consistent with a non-proliferative phenotype. Our data establish CD38 has effects on PCa cell biology independent of its NAD’ase activity as well. As the primary consumer of NAD+, most of the activity of CD38 is devoted to production of ADP-ribose. CD38 also possess cyclase activity and is therefore able to produce cyclic ADP-ribose, a potent calcium mobilizing second messenger. Herein we demonstrate production cADPR by CD38 is active in PCa cell lines and its production is effective in eliciting changes to calcium localization. Changes in calcium localization confer protection from β-lapachone, an ortho naphthoquinone that is cytotoxic to cells when activated by NAD(P)H quinone oxidoreductase 1 (NQO1). Cumulatively, these data establish a novel connection between CD38, modulation of NAD+, and prostate tumor cell metabolism, energy homeostasis, and cell survival.
Prostate cancer
Kridel, Steven J (committee chair)
Singh, Ravi (committee member)
Molina, Anthony (committee member)
Miller, Lance (committee member)
2018-05-24T08:36:08Z (accessioned)
2020-05-23T08:30:20Z (available)
2018 (issued)
Cancer Biology (discipline)
2020-05-23 (terms)
http://hdl.handle.net/10339/90723 (uri)
en (iso)
Wake Forest University

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