NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer

Hong, Soon-Kwang; Cw, Park; Sw, Kim; Nam, YJ; Yu, Jianping; Shin, Jae‐Eun; Chen, Yun; Im, S-H.; Kt, Kim; Sung, YC; Choi, Kyung Hwa

doi:10.1038/onc.2015.415

Cited by 56 publications

(52 citation statements)

References 37 publications

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“…In this study we suggested that SIRT6 can prevent oxidative stress damage in cells through up-regulation of NAMPT activity and increase in NADPH, as a consequence of G6PD activation. This result is in line with a study reporting that, in breast cancer cells, NAMPT activity counteracts glucose deprivation-induced oxidative stress by inducing an increase in NADPH (10). Thus, our observations indicate that SIRT6 is a key upstream player regulating NAMPT activity in these events.…”

Section: Discussionsupporting

confidence: 93%

“…NAMPT inhibition with FK866 also affects the NADP(H) pool, although to a different extent, depending on the cell type (8,9). Notably, in breast cancer cells, the NAMPT-mediated increase in NAD + levels has been shown to be paralleled by an increase in NADPH through the pentose phosphate pathway, resulting in tumor cell protection from glucose deprivation-induced oxidative stress (10).…”

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confidence: 99%

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SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells

et al. 2018

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Nicotinamide phosphoribosyltransferase (NAMPT) is the rate‐limiting enzyme in the NAD+ salvage pathway from nicotinamide. By controlling the biosynthesis of NAD+, NAMPT regulates the activity of NAD+‐converting enzymes, such as CD38, poly‐ADP‐ribose polymerases, and sirtuins (SIRTs). SIRT6 is involved in the regulation of a wide number of metabolic processes. In this study, we investigated the ability of SIRT6 to regulate intracellular NAMPT activity and NAD(P)(H) levels. BxPC‐3 cells and MCF‐7 cells were engineered to overexpress a catalytically active or a catalytically inactive SIRT6 form or were engineered to silence endogenous SIRT6 expression. In SIRT6‐overexpressing cells, NAD(H) levels were up‐regulated, as a consequence of NAMPT activation. By immunopurification and incubation with recombinant SIRT6, NAMPT was found to be a direct substrate of SIRT6 deacetylation, with a mechanism that upregulates NAMPT enzymatic activity. Extracellular NAMPT release was enhanced in SIRT6‐silenced cells. Also glucose‐6‐phosphate dehydrogenase activity and NADPH levels were increased in SIRT6‐overexpressing cells. Accordingly, increased SIRT6 levels reduced cancer cell susceptibility to H2O2‐induced oxidative stress and to doxorubicin. Our data demonstrate that SIRT6 affects intracellular NAMPT activity, boosts NAD(P)(H) levels, and protects against oxidative stress. The use of SIRT6 inhibitors, together with agents inducing oxidative stress, may represent a promising treatment strategy in cancer.—Sociali, G., Grozio, A., Caffa, I., Schuster, S., Becherini, P., Damonte, P., Sturla, L., Fresia, C., Passalacqua, M., Mazzola, F., Raffaelli, N., Garten, A., Kiess, W., Cea, M., Nencioni, A., Bruzzone, S. SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. FASEB J. 33, 3704–3717 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells

et al. 2018

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“…10 In a previous study, we reported that NAMPT could increase the antioxidant capacity of cancer cells and induce cancer cell survival under excessive oxidative stress upon glucose deprivation. 15 Consistently, NAMPT expression was not induced by H 2 O 2 treatment in normal cells, but it was dramatically increased in CRC cells ( Figure 4C), indicating that NAMPT expression in tumor tissues could be increased due to inflammation-induced ROS production. In tissues of CRC patients, both mRNA and protein levels of NAMPT were also upregulated ( Figure 6F-I).…”

Section: Discussionsupporting

confidence: 56%

“…Cancer cells that survive despite oxidative stress are likely to have acquired adaptive mechanisms to counteract the potential toxic effects of elevated ROS . In a previous study, we reported that NAMPT could increase the antioxidant capacity of cancer cells and induce cancer cell survival under excessive oxidative stress upon glucose deprivation . Consistently, NAMPT expression was not induced by H 2 O 2 treatment in normal cells, but it was dramatically increased in CRC cells (Figure C), indicating that NAMPT expression in tumor tissues could be increased due to inflammation‐induced ROS production.…”

Section: Discussionsupporting

confidence: 55%

“…NAMPT is upregulated in various cancer types, including prostate, breast, colorectal, gastric and liver cancers, and could be induced in response to stressors such as genotoxic stress and nutrient deprivation . FK866, a specific inhibitor of NAMPT, has been reported to inhibit breast cancer progression in a xenograft model, and colon cancer progression in an inflammation‐induced model . Cancer cells are reported to have a high rate of NAD + turnover and a low ratio of cytosolic NAD + /NADH due to their elevated metabolic needs .…”

Section: Introductionmentioning

confidence: 99%

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Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level

et al. 2018

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Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+) and a reduced form (NADH). NAD + plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD + and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD +/NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD + salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two‐photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)‐induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT‐mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.

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NAMPT‐Driven M2 Polarization of Tumor‐Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer

Hong,

Lee,

Kim

et al. 2024

Advanced Science

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Nicotinamide phosphoribosyltransferase (NAMPT) is a metabolic enzyme with key roles in inflammation. Previous studies have examined the consequences of its upregulated expression in cancer cells themselves, but studies are limited with respect to its role in the other cells within the tumor microenvironment (TME) during colorectal cancer (CRC) progression. Using single‐cell RNA sequencing (scRNA‐seq) data, it is founded that NAMPT is highly expressed in SPP1+ tumor‐associated macrophages (TAMs), a unique subset of TAMs associated with immunosuppressive activity. A NAMPThigh gene signature in SPP1+ TAMs correlated with worse prognostic outcomes in CRC patients. The effect of Nampt deletion in the myeloid compartment of mice during CRC development is explored. NAMPT deficiency in macrophages resulted in HIF‐1α destabilization, leading to reduction in M2‐like TAM polarization. NAMPT deficiency caused significant decreases in the efferocytosis activity of macrophages, which enhanced STING signaling and the induction of type I IFN‐response genes. Expression of these genes contributed to anti‐tumoral immunity via potentiation of cytotoxic T cell activity in the TME. Overall, these findings suggest that NAMPT‐initiated TAM‐specific genes can be useful in predicting poor CRC patient outcomes; strategies aimed at targeting NAMPT may provide a promising therapeutic approach for building an immunostimulatory TME in CRC progression.

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NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer

Cited by 56 publications

References 37 publications

SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells

SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells

Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level

NAMPT‐Driven M2 Polarization of Tumor‐Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer

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