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

Giovanna Sociali, Alessia Grozio, Irene Caffa, Susanne Schuster, Pamela Becherini, Patrizia Damonte, Laura Sturla, Chiara Fresia, Mario Passalacqua, Francesca Mazzola, Nadia Raffaelli, Antje Garten, Wieland Kiess, Michele Cea, Alessio Nencioni, Santina Bruzzone

Research output: Contribution to journalArticle

Abstract

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 up-regulates 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.

Original languageEnglish
Pages (from-to)fj201800321R
JournalFASEB Journal
DOIs
Publication statusE-pub ahead of print - Dec 4 2018

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Nicotinamide Phosphoribosyltransferase
NAD
Cells
Neoplasms
Oxidative stress
Oxidative Stress
Sirtuins
Salvaging
Niacinamide
Poly(ADP-ribose) Polymerases
Glucosephosphate Dehydrogenase
Biosynthesis
MCF-7 Cells
Enzymes
NADP
Doxorubicin
Up-Regulation
Chemical activation

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Sociali, G., Grozio, A., Caffa, I., Schuster, S., Becherini, P., Damonte, P., ... Bruzzone, S. (2018). SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. FASEB Journal, fj201800321R. https://doi.org/10.1096/fj.201800321R

SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. / Sociali, Giovanna; Grozio, Alessia; Caffa, Irene; Schuster, Susanne; Becherini, Pamela; Damonte, Patrizia; Sturla, Laura; Fresia, Chiara; Passalacqua, Mario; Mazzola, Francesca; Raffaelli, Nadia; Garten, Antje; Kiess, Wieland; Cea, Michele; Nencioni, Alessio; Bruzzone, Santina.

In: FASEB Journal, 04.12.2018, p. fj201800321R.

Research output: Contribution to journalArticle

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 2018, 'SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells', FASEB Journal, pp. fj201800321R. https://doi.org/10.1096/fj.201800321R
Sociali G, Grozio A, Caffa I, Schuster S, Becherini P, Damonte P et al. SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. FASEB Journal. 2018 Dec 4;fj201800321R. https://doi.org/10.1096/fj.201800321R
Sociali, Giovanna ; Grozio, Alessia ; Caffa, Irene ; Schuster, Susanne ; Becherini, Pamela ; Damonte, Patrizia ; Sturla, Laura ; Fresia, Chiara ; Passalacqua, Mario ; Mazzola, Francesca ; Raffaelli, Nadia ; Garten, Antje ; Kiess, Wieland ; Cea, Michele ; Nencioni, Alessio ; Bruzzone, Santina. / SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. In: FASEB Journal. 2018 ; pp. fj201800321R.
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AU - Sociali, Giovanna

AU - Grozio, Alessia

AU - Caffa, Irene

AU - Schuster, Susanne

AU - Becherini, Pamela

AU - Damonte, Patrizia

AU - Sturla, Laura

AU - Fresia, Chiara

AU - Passalacqua, Mario

AU - Mazzola, Francesca

AU - Raffaelli, Nadia

AU - Garten, Antje

AU - Kiess, Wieland

AU - Cea, Michele

AU - Nencioni, Alessio

AU - Bruzzone, Santina

PY - 2018/12/4

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