TY - JOUR TI - NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition AU - Moore, Alexandra M. AU - Zhou, Lei AU - Cui, Jing AU - Li, Luyi AU - Wu, Nanping AU - Yu, Alice AU - Poddar, Soumya AU - Liang, Keke AU - Abt, Evan R. AU - Kim, Stephanie AU - Ghukasyan, Razmik AU - Khachatourian, Nooneh AU - Pagano, Kristina AU - Elliott, Irmina AU - Dann, Amanda M. AU - Riahi, Rana AU - Le, Thuc AU - Dawson, David W. AU - Radu, Caius G. AU - Donahue, Timothy R. T2 - Proceedings of the National Academy of Sciences AB - 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. DA - 2021/02/23/ PY - 2021 DO - 10.1073/pnas.2012469118 DP - www.pnas.org VL - 118 IS - 8 J2 - PNAS LA - en SN - 0027-8424, 1091-6490 UR - https://www.pnas.org/content/118/8/e2012469118 Y2 - 2021/02/17/20:37:51 KW - NAD KW - NAMPT KW - PARP KW - interferon KW - pancreatic cancer ER -