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

Alexandra M. Moore | Zendy; Lei Zhou | Zendy; Jing Cui | Zendy; Luyi Li | Zendy; Nanping Wu | Zendy; Alice C. Yu | Zendy; Soumya Poddar | Zendy; Keke Liang | Zendy; Evan R. Abt | Zendy; Stephanie Kim | Zendy; Razmik Ghukasyan | Zendy; Nooneh Khachatourian | Zendy; Kristina Pagano | Zendy; Irmina A. Elliott | Zendy; Amanda M. Dann | Zendy; Rana Riahi | Zendy; Thuc Le | Zendy; David W. Dawson | Zendy; Caius G. Radu | Zendy; Timothy R. Donahue | Zendy

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

Author(s) -

Alexandra M. Moore,

Lei Zhou,

Jing Cui,

Luyi Li,

Nanping Wu,

Alice C. Yu,

Soumya Poddar,

Keke Liang,

Evan R. Abt,

Stephanie Kim,

Razmik Ghukasyan,

Nooneh Khachatourian,

Kristina Pagano,

Irmina A. Elliott,

Amanda M. Dann,

Rana Riahi,

Thuc Le,

David W. Dawson,

Caius G. Radu,

Timothy R. Donahue

Publication year - 2021

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.2012469118

Subject(s) - nad+ kinase , nicotinamide phosphoribosyltransferase , nicotinamide adenine dinucleotide , cancer research , enzyme , cell growth , biology , signal transduction , in vivo , nicotinamide , pancreatic cancer , cancer cell , chemistry , biochemistry , cancer , genetics , microbiology and biotechnology

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.

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