Clinical cancer research, 2014-01, Vol.20 (1), p.120-130
2014
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- Autor(en) / Beteiligte
- Titel
- Targeting of NAD Metabolism in Pancreatic Cancer Cells: Potential Novel Therapy for Pancreatic Tumors
- Ist Teil von
- Clinical cancer research, 2014-01, Vol.20 (1), p.120-130
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2014
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth. We used human pancreatic cancer cells, both in vitro (cell culture experiments) and in vivo (xenograft experiments), to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth. We demonstrated that pharmacologic and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1 nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo, and further increased the sensitivity to Nampt inhibition. Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-0432eISSN: 1557-3265DOI: 10.1158/1078-0432.ccr-13-0150Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3947324
- Format
- –
- Schlagworte
- Acrylamides - pharmacology, ADP-ribosyl Cyclase 1 - metabolism, Animals, Antineoplastic agents, Antineoplastic Agents - pharmacology, Biological and medical sciences, Cell Line, Tumor, Cell Proliferation - drug effects, Cell Survival - drug effects, Cytokines - antagonists & inhibitors, Cytokines - metabolism, Female, Gastroenterology. Liver. Pancreas. Abdomen, Humans, Liver. Biliary tract. Portal circulation. Exocrine pancreas, Medical sciences, Membrane Glycoproteins - metabolism, Mice, Mice, Nude, Molecular Targeted Therapy, Multiple tumors. Solid tumors. Tumors in childhood (general aspects), NAD - metabolism, Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors, Nicotinamide Phosphoribosyltransferase - metabolism, Pancreatic Neoplasms - drug therapy, Pancreatic Neoplasms - metabolism, Pancreatic Neoplasms - pathology, Pharmacology. Drug treatments, Piperidines - pharmacology, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases - metabolism, Sirtuin 1 - metabolism, Tumor Burden - drug effects, Tumors, Xenograft Model Antitumor Assays