Nadk, short for nicotinamide adenine dinucleotide (NAD+) kinase, is the sole enzyme that phosphorylates NAD+ to produce nicotinamide adenine dinucleotide phosphate (NADP). This reaction is crucial as NADP(H) provides the reducing power in anabolic pathways. NADK genes and the NADP(H)-producing mechanism are evolutionarily conserved across archaea, bacteria, plants, and mammals [1,7]. Genetic models have been instrumental in validating its essential role in cellular redox homeostasis and metabolism in multicellular organisms [1].

In breast cancer, NADK-mediated de novo NADP(H) synthesis is essential for metastasis. Metastatic signals epigenetically regulate the NADK promoter, increasing its levels in metastatic cells [2]. In pancreatic ductal adenocarcinoma, oncogenic KRAS promotes NADK phosphorylation, hyper-activating it to sustain NADP+ and NADPH levels [3]. In the razor clam, under high-salinity stress, ScNADK is upregulated, and its knockdown reduces proline content and the expression of key proline-synthetase genes, indicating its role in osmoregulation [4]. In lung adenocarcinoma, knockdown of Nadk promotes ferroptosis by regulating the NADPH/FSP1 axis, and Nadk is over-expressed in patients [5]. In non-small cell lung carcinoma, NUAK1-mediated phosphorylation of NADK mitigates ROS accumulation and promotes osimertinib resistance [6].

In conclusion, Nadk plays essential roles in multiple biological processes and disease conditions. Model-based research, especially gene-knockout studies, has revealed its significance in cancer metastasis, metabolic adaptation in tumors, osmoregulation in marine organisms, and drug resistance in lung cancer. Understanding Nadk's functions offers potential therapeutic targets for metastatic breast cancer, pancreatic cancer, and non-small cell lung carcinoma.

References:

1. Oka, Shin-Ichi, Titus, Allen Sam, Zablocki, Daniela, Sadoshima, Junichi. 2022. Molecular properties and regulation of NAD+ kinase (NADK). In Redox biology, 59, 102561. doi:10.1016/j.redox.2022.102561. https://pubmed.ncbi.nlm.nih.gov/36512915/

2. Ilter, Didem, Drapela, Stanislav, Schild, Tanya, McReynolds, Melanie R, Gomes, Ana P. 2023. NADK-mediated de novo NADP(H) synthesis is a metabolic adaptation essential for breast cancer metastasis. In Redox biology, 61, 102627. doi:10.1016/j.redox.2023.102627. https://pubmed.ncbi.nlm.nih.gov/36841051/

3. Schild, Tanya, McReynolds, Melanie R, Shea, Christie, Gomes, Ana P, Blenis, John. . NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma. In Cell reports, 35, 109238. doi:10.1016/j.celrep.2021.109238. https://pubmed.ncbi.nlm.nih.gov/34133937/

4. Liu, Ruiqi, Deng, Min, Zhang, Na, Jia, Liang, Niu, Donghong. 2024. NADK-mediated proline synthesis enhances high-salinity tolerance in the razor clam. In Comparative biochemistry and physiology. Part A, Molecular & integrative physiology, 291, 111610. doi:10.1016/j.cbpa.2024.111610. https://pubmed.ncbi.nlm.nih.gov/38408517/

5. Meng, Xiangpeng, Peng, Fang, Yu, Shijie, Wang, Wenchi, Shao, Shujuan. 2024. Knockdown of NADK promotes LUAD ferroptosis via NADPH/FSP1 axis. In Journal of cancer research and clinical oncology, 150, 228. doi:10.1007/s00432-024-05752-z. https://pubmed.ncbi.nlm.nih.gov/38700533/

6. Lin, Wei, Wang, Na, Wu, Shihao, Liao, Yongde, Meng, Yunchong. . NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma. In Cancer research, 84, 4081-4098. doi:10.1158/0008-5472.CAN-24-0249. https://pubmed.ncbi.nlm.nih.gov/39159134/

7. Vickman, Oliver, Erives, Albert. 2019. Episodic evolution of a eukaryotic NADK repertoire of ancient provenance. In PloS one, 14, e0220447. doi:10.1371/journal.pone.0220447. https://pubmed.ncbi.nlm.nih.gov/31369599/