NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition
Menée in vitro et à l'aide d'un modèle murin de cancer du pancréas, cette étude met en évidence un mécanisme par lequel la signalisation de l'interféron de type 1 augmente la consommation de NAD par les enzymes PARP9, PARP10 et PARP14 et sensibilise les cellules cancéreuses à l'inhibition de la nicotinamide phosphoribosyltransférase
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which NAD and its reduced form NADH are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, increases consumption of NAD(H) through upregulation of PARP9, PARP10, and PARP14. This NAD(H) consumption results in increased dependence upon NAMPT for the recycling of NAM to salvage NAD pools, thus sensitizing these tumor cells to treatment with pharmacologic NAMPT inhibition by decreasing PDAC cell proliferation and invasion in vitro and suppressing orthotopic tumor growth and liver metastases in vivo through this mechanism.Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.All study data are included in the article and/or supporting information.