@article{3bee99ce154f4c81bf135ea6b2a918e2,
title = "NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma",
abstract = "Metabolic adaptations and the signaling events that control them promote the survival of pancreatic ductal adenocarcinoma (PDAC) at the fibrotic tumor site, overcoming stresses associated with nutrient and oxygen deprivation. Recently, rewiring of NADPH production has been shown to play a key role in this process. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells. However, de novo NADP+ is synthesized only through one known enzymatic reaction, catalyzed by NAD+ kinase (NADK). In this study, we show that oncogenic KRAS promotes protein kinase C (PKC)-mediated NADK phosphorylation, leading to its hyperactivation, thus sustaining both NADP+ and NADPH levels in PDAC cells. Together, our data show that increased NADK activity is an important adaptation driven by oncogenic signaling. Our findings indicate that NADK could serve as a much-needed therapeutic target for PDAC.",
keywords = "KRAS, NADK, NADP+, NADPH, PDAC, PKC",
author = "Tanya Schild and McReynolds, {Melanie R.} and Christie Shea and Vivien Low and Schaffer, {Bethany E.} and Asara, {John M.} and Elena Piskounova and Noah Dephoure and Rabinowitz, {Joshua D.} and Gomes, {Ana P.} and John Blenis",
note = "Funding Information: We are grateful to the Blenis and Cantley lab members for helpful discussions on the project. We are also thankful to Dr. Gina Lee and Adam Rosenzweig for technical assistance. We are grateful to Dr. Gerta Hoxhaj for technical advice and Dr. Brendan Manning for the NADK lentiviral constructs. We thank Dr. Gina DeNicola for kindly gifting us KP MEFs. We thank Dr. Lukas Dow for Kras +/LSL-G12D mice and for Tp53 CRISPR-Cas9 sgRNA lentivirus and Dr. Maria Paz Zafra Martin for technical advice on organoids. T.S. was supported by the NIH F31 pre-doctoral fellowship 1F31CA220750-01 . A.P.G. was supported by a Susan G. Komen Postdoctoral Fellowship and a Pathway to Independence Award from NCI ( K99CA218686 ). M.R.M. is supported by both the Hanna H. Gray Fellows Program of the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program (PDEP) of the Burroughs Welcome Fund . This research was supported by NIH grants RO1GM51405 and RO1CA46595 to J.B. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = jun,
day = "15",
doi = "10.1016/j.celrep.2021.109238",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}