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NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition.

Authors :
Moore, Alexandra M.
Lei Zhou
Jing Cui
Luyi Li
Nanping Wu
Yu, Alice
Poddar, Soumya
Liang, Keke
Abt, Evan R.
Kim, Stephanie
Ghukasyan, Razmik
Khachatourian, Nooneh
Pagano, Kristina
Elliott, Irmina
Dann, Amanda M.
Riahi, Rana
Le, Thuc
Dawson, David W.
Radu, Caius G.
Donahue, Timothy R.
Source :
Proceedings of the National Academy of Sciences of the United States of America. 2/23/2021, Vol. 118 Issue 8, p1-11. 11p.
Publication Year :
2021

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
118
Issue :
8
Database :
Academic Search Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
149239425
Full Text :
https://doi.org/10.1073/pnas.2012469118