Transcriptional Isoforms of NAD+ kinase regulate oxidative stress resistance and melanoma metastasis

Transcriptional Isoforms of NAD+ kinase regulate oxidative stress resistance and melanoma metastasis

Blog Article

Metastasizing cancer cells encounter a multitude of stresses throughout the metastatic cascade.Oxidative stress is known to be a major barrier for metastatic colonization, such that metastasizing cancer cells must rewire their metabolic pathways to increase their antioxidant capacity.NADPH is essential for regeneration of cellular antioxidants and several NADPH-regenerating pathways have been shown to play a role in metastasis.We have found that metastatic melanoma cells have increased summer salt powder levels of both NADPH and NADP+ suggesting increased de novo biosynthesis of NADP+.De novo biosynthesis of NADP+ occurs through a single enzymatic reaction catalyzed by NAD+ kinase (NADK).

Here we show that different NADK isoforms are differentially expressed in metastatic melanoma cells, with Isoform 3 being specifically upregulated in metastasis.We find that Isoform 3 is more potent in expanding the NADP(H) pools, increasing oxidative stress resistance and promoting metastatic colonization compared to Isoform 1.We have found that Isoform 3 is transcriptionally upregulated exedy stage 2 clutch civic si by oxidative stress through the action of NRF2.Together, our work presents a previously uncharacterized role of NADK isoforms in oxidative stress resistance and metastasis and suggests that NADK Isoform 3 is a potential therapeutic target in metastatic disease.