Intracellular NAD+ depletion enhances bortezomib-induced anti-myeloma activity

Cagnetta, Antonia; Cea, Michele; Calimeri, Teresa; Acharya, Chirag; Fulciniti, Mariateresa; Tai, Yu Tzu; Hideshima, Teru; Chauhan, Dharminder; Zhong, Mike Y; Patrone, Franco; Nencioni, Alessio; Gobbi, Marco; Richardson, Paul G.; Munshi, Nikhil C.; Anderson, Kenneth C.

doi:10.1182/blood-2013-02-483511

Cited by 77 publications

(77 citation statements)

References 42 publications

(52 reference statements)

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“…It was previously shown that blockage of the NAD + salvage pathways using the NAMPT inhibitor FK866 induces autophagic death in neuroblastoma SH-SY5Y cells and multiple myeloma cells. [19][20][21] Recent data show that FK866 activates AMPK (adenosine monophosphateactivated protein kinase) and downregulates mammalian target of rapamycin (mTOR) signalling in hepatocarcinoma cells. 22 In view of the important role NAD + has in modulating p53 activity (via NAD + -dependent SIRTs) 23,24 and our recent demonstration that the NAD + synthesizing enzyme NMNAT2 is a downstream target of p53, 16 we wished to first determine if FK866-induced cell death was p53-dependent.…”

Section: Resultsmentioning

confidence: 99%

“…The demonstration that similar results can be achieved by NAMPT KD confirms that NAMPT is specifically targeted by FK866. That inhibition of NAMPT (and hence the NAD + salvage pathway) results in autophagy and cell death has recently been reported; [20][21][22] however, the precise underlying mechanisms are unclear. Our results show that this is at least, in part, due to increased p73 levels as KD of p73 in FK866-treated cells effectively reverses the effects of FK866 on autophagy and cell survival.…”

Section: 33mentioning

confidence: 99%

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The NAD+ salvage pathway modulates cancer cell viability via p73

et al. 2015

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The involvement of the nicotinamide adenine dinucleotide (NAD + ) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD + salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD + salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition-induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment.

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Section: Resultsmentioning

confidence: 99%

Section: 33mentioning

confidence: 99%

The NAD+ salvage pathway modulates cancer cell viability via p73

et al. 2015

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“…While intracellular NAD + protects cells against PARP-1-dependent cell death and possibly also against some forms of apoptosis [59][60][61] and autophagy, 60,62 it has an opposite role in promoting necroptosis. NAD + may therefore represent an important intracellular factor regulating the choice of cell demise, a finding that may call for caution in the clinical translation of pharmacological and nutraceutical approaches Figure 7 Cambinol protects from renal ischemia/reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

et al. 2015

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Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD + ) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD + promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD + -dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD + does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors. + as a substrate in a number of regulatory processes has shed a new light on its role in cell physiology. Indeed, NAD + represents a substrate for a wide range of enzymes including cADP-ribose synthases, poly (ADP-ribose) polymerases (PARPs) and the sirtuin family of NAD + -dependent deacylases (SIRTs). In marked contrast to its role in energy metabolism, the involvement of NAD + in these enzymatic reactions is based on its ability to function as a donor of ADP-ribose, a reaction that, if sustained, can lead to the depletion of the intracellular NAD + pool. 1-5The pro-survival role of NAD + has been particularly well described in cells exposed to genotoxic/oxidative stress. In response to DNA damage, PARP1, the founding and most abundant member of the PARP family, binds to DNA strand breaks and initiates a repair response by catalyzing the posttranslational modification of several nuclear proteins, including itself. This protective response is characterized by the transfer of successive units of the ADP-ribose moiety (up to 200 units) from NAD + to other proteins, compromising therefore both energy production (slowing the rate of glycolysis, electron transport and ATP formation) and activity of other NAD + -dependent enzymes through NAD + depletion. 6,7 Moreover, PARP1-synthesized PAR polymers can be degraded into free oligomers, known to translocate to the mitochondria where they can trigger the release of AIF from mitochondria to the nucleus. [8][9][10][11] The precise molecular steps linking PARP1 activation to this form of stress-induced cell death, termed parthanatos, have not been fully elucidated, and...

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“…Nampt-targeting emerges as effective approach not only when coupled to standard chemotherapy, including DNA damaging agents [16] but also in combination with more modern, molecularly-targeted agents (such as ibrutinib, cyclosporin A and bortezomib) [8,9,13].…”

Section: Nampt Inhibitorsmentioning

confidence: 99%

“…As a result, Nampt inhibitors as monotherapy have demonstrated potent antitumor activity in preclinical cancer models [3][4][5][6][7]. In such a scenario, investigators have also tested NAD + -depleting agents in combination with antineoplastic agents, chemotherapy, or radiotherapy in a wide range of hematological malignancies, including AML, MM, and lymphomas, observing an increased activity and overall tolerability of these agents [8][9][10][11][12]. Thus, several clinical trials are currently exploring such metabolic vulnerability in patients undergoing chemotherapy (NCT02702492, NCT00435084, and NCT00431912).…”

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confidence: 99%