Lactate drives CD38 signaling to promote Epithelial-Mesenchymal Transition through Snail induction in non-small cell lung cancer cells

CD38 is the main NADase in mammalian cells. It regulates the homeostasis of nicotinamide adenine dinucleotide (NAD+) and extracellular nucleotides. Its function plays an important role in infection and aging. However, its potential functions in tumor cells have not been fully elucidated. In the present study, we demonstrated that lactate, which is derived from tumor metabolism remodeling, upregulates the expression of CD38 through OXPHOS-driven Hippo-TAZ pathway. The highly expressed CD38 converts NAD + to adenosine through the CD203a/CD73 complex and adenosine binds and activates its receptor A2AR, inducing the expression of Snail and promoting the invasion and metastasis of lung cancer cells. This finding elucidates a new perspective on the interplay between NAD + metabolism and glycolysis in tumor development. Lactic acid derived from tumor metabolic reprogramming upregulates the expression of CD38 through the OXPHOS-driven Hippo-TAZ pathway, promoting the conversion of nicotinamide adenine dinucleotide (NAD+) to adenosine and activating adenosine receptors. The activated adenosine receptors induce the expression of Snail through the Akt-Gsk3 beta pathway, promoting the progression of EMT in lung cancer cells. image