Title | NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Schild, T, McReynolds, MR, Shea, C, Low, V, Schaffer, BE, Asara, JM, Piskounova, E, Dephoure, N, Rabinowitz, JD, Gomes, AP, Blenis, J |
Journal | Cell Rep |
Volume | 35 |
Issue | 11 |
Pagination | 109238 |
Date Published | 2021 Jun 15 |
ISSN | 2211-1247 |
Keywords | Adenocarcinoma, 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> |
DOI | 10.1016/j.celrep.2021.109238 |
Alternate Journal | Cell Rep |
PubMed ID | 34133937 |
Grant List | F31 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 |