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

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

doi:10.1073/pnas.2012469118

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

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

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Article number	e2012469118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	8
DOIs	https://doi.org/10.1073/pnas.2012469118
State	Published - Feb 23 2021
Externally published	Yes

Keywords

Interferon
NAD
NAMPT
PARP
Pancreatic cancer

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.2012469118

Cite this

Moore, A. M., Zhou, L., Cui, J., Li, L., Wu, N., Yu, A., Poddar, S., Liang, K., Abt, E. R., Kim, S., Ghukasyan, R., Khachatourian, N., Pagano, K., Elliott, I., Dann, A. M., Riahi, R., Le, T., Dawson, D. W., Radu, C. G., & Donahue, T. R. (2021). NAD⁺ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition. Proceedings of the National Academy of Sciences of the United States of America, 118(8), Article e2012469118. https://doi.org/10.1073/pnas.2012469118

Moore, AM, Zhou, L, Cui, J, Li, L, Wu, N, Yu, A, Poddar, S, Liang, K, Abt, ER, Kim, S, Ghukasyan, R, Khachatourian, N, Pagano, K, Elliott, I, Dann, AM, Riahi, R, Le, T, Dawson, DW, Radu, CG & Donahue, TR 2021, 'NAD⁺ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 8, e2012469118. https://doi.org/10.1073/pnas.2012469118

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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.",

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AU - Moore, Alexandra M.

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AU - Cui, Jing

AU - Li, Luyi

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AU - Yu, Alice

AU - Poddar, Soumya

AU - Liang, Keke

AU - Abt, Evan R.

AU - Kim, Stephanie

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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.

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