Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells.
Tumor cells have increased metabolic requirements to maintain rapid growth. In particular, a highly lipogenic phenotype is a hallmark of many tumor types, including prostate. Cancer cells also have increased turnover of nicotinamide adenine dinucleotide (NAD(+)), a coenzyme involved in multiple meta...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3387004?pdf=render |
| _version_ | 1819019885934542848 |
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| author | Sarah C Bowlby Michael J Thomas Ralph B D'Agostino Steven J Kridel |
| author_facet | Sarah C Bowlby Michael J Thomas Ralph B D'Agostino Steven J Kridel |
| author_sort | Sarah C Bowlby |
| collection | DOAJ |
| description | Tumor cells have increased metabolic requirements to maintain rapid growth. In particular, a highly lipogenic phenotype is a hallmark of many tumor types, including prostate. Cancer cells also have increased turnover of nicotinamide adenine dinucleotide (NAD(+)), a coenzyme involved in multiple metabolic pathways. However, a specific role for NAD(+) in tumor cell lipogenesis has yet to be described. Our studies demonstrate a novel role for the NAD(+)-biosynthetic enzyme Nicotinamide phosphoribosyltransferase (Nampt) in maintaining de novo lipogenesis in prostate cancer (PCa) cells. Inhibition of Nampt reduces fatty acid and phospholipid synthesis. In particular, short chain saturated fatty acids and the phosphatidylcholine (PC) lipids into which these fatty acids are incorporated were specifically reduced by Nampt inhibition. Nampt blockade resulted in reduced ATP levels and concomitant activation of AMP-activated protein kinase (AMPK) and phosphorylation of acetyl-CoA carboxylase (ACC). In spite of this, pharmacological inhibition of AMPK was not sufficient to fully restore fatty acid synthesis. Rather, Nampt blockade also induced protein hyperacetylation in PC-3, DU145, and LNCaP cells, which correlated with the observed decreases in lipid synthesis. Moreover, the sirtuin inhibitor Sirtinol, and the simultaneous knockdown of SIRT1 and SIRT3, phenocopied the effects of Nampt inhibition on fatty acid synthesis. Altogether, these data reveal a novel role for Nampt in the regulation of de novo lipogenesis through the modulation of sirtuin activity in PCa cells. |
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| format | Article |
| id | doaj.art-f15d548e250040ac91c57d3dfa22aaea |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T03:42:26Z |
| publishDate | 2012-01-01 |
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| series | PLoS ONE |
| spelling | doaj.art-f15d548e250040ac91c57d3dfa22aaea2022-12-21T19:17:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0176e4019510.1371/journal.pone.0040195Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells.Sarah C BowlbyMichael J ThomasRalph B D'AgostinoSteven J KridelTumor cells have increased metabolic requirements to maintain rapid growth. In particular, a highly lipogenic phenotype is a hallmark of many tumor types, including prostate. Cancer cells also have increased turnover of nicotinamide adenine dinucleotide (NAD(+)), a coenzyme involved in multiple metabolic pathways. However, a specific role for NAD(+) in tumor cell lipogenesis has yet to be described. Our studies demonstrate a novel role for the NAD(+)-biosynthetic enzyme Nicotinamide phosphoribosyltransferase (Nampt) in maintaining de novo lipogenesis in prostate cancer (PCa) cells. Inhibition of Nampt reduces fatty acid and phospholipid synthesis. In particular, short chain saturated fatty acids and the phosphatidylcholine (PC) lipids into which these fatty acids are incorporated were specifically reduced by Nampt inhibition. Nampt blockade resulted in reduced ATP levels and concomitant activation of AMP-activated protein kinase (AMPK) and phosphorylation of acetyl-CoA carboxylase (ACC). In spite of this, pharmacological inhibition of AMPK was not sufficient to fully restore fatty acid synthesis. Rather, Nampt blockade also induced protein hyperacetylation in PC-3, DU145, and LNCaP cells, which correlated with the observed decreases in lipid synthesis. Moreover, the sirtuin inhibitor Sirtinol, and the simultaneous knockdown of SIRT1 and SIRT3, phenocopied the effects of Nampt inhibition on fatty acid synthesis. Altogether, these data reveal a novel role for Nampt in the regulation of de novo lipogenesis through the modulation of sirtuin activity in PCa cells.http://europepmc.org/articles/PMC3387004?pdf=render |
| spellingShingle | Sarah C Bowlby Michael J Thomas Ralph B D'Agostino Steven J Kridel Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells. PLoS ONE |
| title | Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells. |
| title_full | Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells. |
| title_fullStr | Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells. |
| title_full_unstemmed | Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells. |
| title_short | Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells. |
| title_sort | nicotinamide phosphoribosyl transferase nampt is required for de novo lipogenesis in tumor cells |
| url | http://europepmc.org/articles/PMC3387004?pdf=render |
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