NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma.

Autor:	Schild T; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA., McReynolds MR; Department of Chemistry, Princeton University, Princeton, NJ 08540, USA., Shea C; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA; Tri-institutional PhD Program in Chemical Biology, New York, NY 10021, USA., Low V; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA., Schaffer BE; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA., Asara JM; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA., Piskounova E; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA; Department of Dermatology, Weill Cornell Medicine, New York, NY 10021, USA., Dephoure N; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA., Rabinowitz JD; Department of Chemistry, Princeton University, Princeton, NJ 08540, USA., Gomes AP; Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: ana.gomes@moffitt.org., Blenis J; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: job2064@med.cornell.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Jun 15; Vol. 35 (11), pp. 109238.
DOI:	10.1016/j.celrep.2021.109238
Abstrakt:	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. Competing Interests: Declaration of interests J.D.R. is a founder of Raze Therapeutics and advisor to L.E.A.F. Pharmaceuticals, Pfizer, Agios Pharmaceuticals, Kadmon Pharmaceuticals, and Rafael Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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