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The NAMPT inhibitor FK866 increases metformin sensitivity in pancreatic cancer cells

ABSTRACT: The NAMPT inhibitor FK866 increases metformin sensitivity in pancreatic cancer cells

PROVIDER: PRJNA866164 | ENA |

REPOSITORIES: ENA

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The NAMPT inhibitor FK866 increases metformin sensitivity in pancreatic cancer cells

Project description:Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use was associated with reduced pancreatic cancer incidence or better survival in diabetics. Metformin has been shown to inhibit PDAC cells survival and growth in vitro and in vivo. However, clinical trials using metformin failed to decrease pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirm that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio turned PDAC cells resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cells xenografts but not in mice with PANC1 xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress providing new insights about the mechanisms leading to cancer cell death.

2023-06-01 | GSE210562 | GEO

RNA-sequencing of murine B16F10 melanoma cells with IFNg and FK866, a Nampt inhibitor

Project description:NAMPT is expressed in all cells during normal cell homeostasis. However, melanoma cells have a higher energetic demand and increase NAMPT expression. Our data show that IFNg signaling upregulates NAMPT in both human and mouse melanoma cells leading to increased cell growth and expression kinetics. The purpose of this experiment was to identify how IFNg inducible Nampt alters cell kinetics and we did this by treating melanoma cells with the combination of IFNg and FK866.

2023-07-01 | GSE207060 | GEO

Molecular sequelae of Nampt Inhibition in Human Multiple Myeloma cell line

Project description:Evaluation of specific coordinated pattern of transcriptional events consistent with anti-myeloma activity of FK866 (chemical Nampt inhibitor) 3 samples were analyzed using as control the untreated cells. Treated cells were cultured in presence of FK866 at concentration of 10nM for 6 and 24 hours.

2012-11-05 | E-GEOD-35414 | biostudies-arrayexpress

Molecular sequelae of Nampt Inhibition in Human Multiple Myeloma cell line

Project description:Evaluation of specific coordinated pattern of transcriptional events consistent with anti-myeloma activity of FK866 (chemical Nampt inhibitor)

2012-11-05 | GSE35414 | GEO

The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells.

Project description:Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use has been associated with reduced pancreatic cancer incidence and better survival in diabetics. Metformin has been shown to inhibit PDAC cells growth and survival, both in vitro and in vivo. However, clinical trials using metformin have failed to reduce pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirmed that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio, and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio caused PDAC cells to be resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression, increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased the cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cell line xenografts, but not in mice with PANC-1 cell line xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress, providing new insights about the mechanisms leading to cancer cell death.

| S-EPMC9688551 | biostudies-literature

The role of nicotinamide phosphoribosyltransferase (Nampt) in hippocampal neural stem/progenitor cells

Project description:Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines. Total RNA obtained from neurospheres derived from postnatal hippocampi subjected to 48 hours in vitro of incubation with Nampt-specific inhibitor FK866 (10 nM, 4 samples) or vehicle (DMSO, 1:1000, 4 samples).

2014-05-08 | E-GEOD-49784 | biostudies-arrayexpress

PPM1D Mutations Silence NAPRT Gene Expression and Confer NAMPT Inhibitor Sensitivity in Glioma

Project description:PPM1D Mutations Silence NAPRT Gene Expression and Confer NAMPT Inhibitor Sensitivity in Glioma

| PRJNA554122 | ENA

RNA-sequencing of murine B16F10 melanoma cells with IFNg and FK866, a Nampt inhibitor

Project description:RNA-sequencing of murine B16F10 melanoma cells with IFNg and FK866, a Nampt inhibitor

| PRJNA853383 | ENA

Inhibiting phosphatidylcholine remodeling in adipose tissue increases insulin sensitivity

Project description:Inhibiting phosphatidylcholine remodeling in adipose tissue increases insulin sensitivity

| PRJNA985667 | ENA

RNA-seq of control and FK866-treated ILC2s in vitro

Project description:To investigate the effect of NAD+ metabolism on ILC2s function, sorted ILC2s from the gut were treated with NAMPT inhibitor FK866 for bulk RNA sequcecing.

2022-11-22 | GSE218368 | GEO

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