1,25(OH)2D3 inhibits Lewis lung cancer cell migration via NHE1-sensitive metabolic reprograming

High prevalence and metastasis rates are characteristics of lung cancer. Glycolysis provides energy for the development and metastasis of cancer cells. The 1,25-dihydroxy vitamin D3 (1,25(OH)₂D₃) has been linked to reducing cancer risk and regulates various physiological functions. We hypothesized that 1,25(OH)₂D₃ could be associated with the expression and activity of Na⁺/H⁺ exchanger isoform 1 (NHE1) of Lewis lung cancer cells, thus regulating glycolysis as well as migration by actin reorganization. Followed by online public data analysis, Vitamin D3 receptor, the receptor of 1,25(OH)₂D₃ has been proved to be abundant in lung cancers. We demonstrated that 1,25(OH)₂D₃ treatment suppressed transcript levels, protein levels, and activity of NHE1 in LLC cells. Furthermore, 1,25(OH)₂D₃ treatment resets the metabolic balance between glycolysis and OXPHOS, mainly including reducing glycolytic enzymes expression and lactate production. In vivo experiments showed the inhibition effects on tumor growth as well. Therefore, we concluded that 1,25(OH)₂D₃ could amend the NHE1 function, which leads to metabolic reprogramming and cytoskeleton reconstruction, finally inhibits the cell migration.