Abstract
NAD salvage is one of the pathways used to generate NAD in mammals. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway, uses nicotinamide (NAM) to generate nicotinamide mononucleotide (NMN). NMN is one of the main precursors of NAD synthesis in cells. Our previous study showed the importance of NAMPT in maintaining NAD levels in pancreatic ductal adenocarcinoma cells (PDAC), and that the NAMPT inhibitor FK866 decreased pancreatic cancer growth. We now tested the effect of STF-118804, a new highly specific NAMPT inhibitor, in models of pancreatic ductal adenocarcinoma. STF-118804 reduced viability and growth of different PDAC lines, as well as the formation of colonies in soft agar. In addition, STF-118804 decreased glucose uptake, lactate excretion, and ATP levels, resulting in metabolic collapse. STF-118804 treatment activated AMPK and inhibited of mTOR pathways in these cells. This effect was significantly potentiated by pharmacological AMPK activation and mTOR inhibition. Exogenous NMN blocked both the activation of the AMPK pathway and the decrease in cell viability. Panc-1 cells expressing GFP-luciferase were orthotopically implanted on mice pancreas to test the in vivo effectiveness of STF-118804. Both STF-118804 and FK866 reduced tumor size after 21 days of treatment. Combinations of STF-118804 with chemotherapeutic agents such as paclitaxel, gemcitabine, and etoposide showed an additive effect in decreasing cell viability and growth. In conclusion, our preclinical study shows that the NAMPT inhibitor STF-118804 reduced the growth of PDAC in vitro and in vivo and had an additive effect in combination with main current chemotherapeutic drugs.
Highlights
NAD is crucial for cell metabolism, participating as a cofactor in redox reactions as well as being a substrate for NAD+-degrading enzymes such as sirtuins, poly(ADPribose) polymerases (PARPs), and NAD+ases like CD38[1]
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by local invasion and metastasis in the lymph nodes www.impactjournals.com/oncotarget and distant sites
Our group showed for the first time that NAD metabolism is an important pathway to target in pancreatic ductal adenocarcinoma cells (PDAC) and that Nicotinamide phosphoribosyltransferase (NAMPT) is crucial to maintain PDAC NAD metabolism
Summary
NAD is crucial for cell metabolism, participating as a cofactor in redox reactions as well as being a substrate for NAD+-degrading enzymes such as sirtuins, poly(ADPribose) polymerases (PARPs), and NAD+ases like CD38[1]. NAD levels are maintained via an equilibrium between its synthesis and degradation. NAD is synthesized via the de novo pathway from tryptophan, the majority of the cellular NAD synthesis in most mammalian tissues comes from the NAD salvage pathway, which uses Nicotinic Acid (NA) or nicotinamide (NAM). Because of the high rate of NAD degradation, the conversion of NAM into nicotinamide mononucleotide (NMN) is the most effective pathway to maintain NAD levels in most tissues [3]. Pancreatic ductal adenocarcinoma (PDA) is predicted to become the second leading cancer-related cause of death by 2020. This disease has an extremely poor prognosis, with current 5-year survival rate of less than 5% despite efforts to find new therapies. Secondary therapeutic failure and resistance to available drugs are pitfalls of chemotherapy for this type of cancer, making it necessary to find new targets and drugs that could treat PDAC [11, 12, 13]
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