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

TitleNADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma.
Publication TypeJournal Article
Year of Publication2021
AuthorsSchild, T, McReynolds, MR, Shea, C, Low, V, Schaffer, BE, Asara, JM, Piskounova, E, Dephoure, N, Rabinowitz, JD, Gomes, AP, Blenis, J
JournalCell Rep
Volume35
Issue11
Pagination109238
Date Published2021 06 15
ISSN2211-1247
KeywordsAdenocarcinoma, Animals, Biosynthetic Pathways, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Proliferation, Female, HEK293 Cells, Humans, Male, Mice, Inbred C57BL, Mice, Nude, NADP, Pancreatic Neoplasms, Phosphorylation, Phosphoserine, Phosphotransferases (Alcohol Group Acceptor), Protein Kinase C, Proto-Oncogene Proteins p21(ras), Signal Transduction
Abstract

<p>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.</p>

DOI10.1016/j.celrep.2021.109238
Alternate JournalCell Rep
PubMed ID34133937
Grant ListF31 CA220750 / CA / NCI NIH HHS / United States
K99 CA218686 / CA / NCI NIH HHS / United States
T32 GM008539 / GM / NIGMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States