The NAD+ salvage pathway modulates cancer cell viability via p73

Abstract

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.

Nicotinamide Phosphoribosyltransferase Inhibitor APO866 Prevents IL-1β-Induced Human Nucleus Pulposus Cell Degeneration via Autophagy

“…Grozio et al reported that NMN can reverse Nampt inhibition induced tumor cell death [63]. Sharif et al reported Nampt inhibition enhances autophagy and breast cancer cell death, however, this effect can be effectively reversed by NMN [64]. In this study, we treated NP cells with NMN or rNampt with or without APO866, and we found that both NMN and rNampt can inhibit the cell autophagy induced by APO866.…”

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

“…More potent PARP1 inhibitors, such as PJ34, DPQ, and the marketed drugs olaparib and rucaparib sensitize tumors to DNA damage, although the drugs have limited use because of toxicity (Alano et al, 2010; Almeida et al, 2017; Mathews and Berk, 2008). Inhibitors of NAMPT, such as FK866 and KPT-9274, selectively kills cancer cells, and are currently being tested for efficacy in patients with solid malignancies (Chini et al, 2014; Poljsak, 2016; Sharif et al, 2016). Inhibition of indoleamine 2,3-dioxygenase (IDO), which mediates the first step in the conversion of tryptophan in de novo NAD + synthesis, shows promise in mice as an antitumor therapeutic target (Friberg et al, 2002; Muller et al, 2005; Uyttenhove et al, 2003).…”

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…Metabolic regulation by p53 family appears a key function for their cancer-related but also ageing-related phenotype. All the three members promote mitochondrial respiration thought regulation of different metabolic enzymes, including the glutaminase 2 (Gls2) (Adamovich et al, 2014;Amelio et al, 2014b;Bellomaria et al, 2010Bellomaria et al, , 2012Giacobbe et al, 2013;He et al, 2013;Hu et al, 2010;Sharif et al, 2015;Simon et al, 2014;Velletri et al, 2013;Viticchie et al, 2015). Gls2 regulates glutamine utilization, supplying anaplerotic flux of substrates resulting in promotion of mitochondrial activity and ATP synthesis (Amelio et al, 2014a;Maniam et al, 2015).…”