NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma
Tanya Schild,
Melanie R. McReynolds,
Christie Shea,
Vivien Low,
Bethany E. Schaffer,
John M. Asara,
Elena Piskounova,
Noah Dephoure,
Joshua D. Rabinowitz,
Ana P. Gomes,
John Blenis
Affiliations
Tanya Schild
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
Melanie R. McReynolds
Department of Chemistry, Princeton University, Princeton, NJ 08540, USA
Christie Shea
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
Vivien Low
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
Bethany E. Schaffer
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
John M. Asara
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Elena Piskounova
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
Noah Dephoure
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA
Joshua D. Rabinowitz
Department of Chemistry, Princeton University, Princeton, NJ 08540, USA
Ana P. Gomes
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Corresponding author
John Blenis
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA; Corresponding author
Summary: 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.
