1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)₂D₃ in NSCLC Treatment

1,25-dihydroxyvitamin D₃ (1,25(OH)₂ D₃ ) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDR^high ) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDR^low and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH)₂ D₃ sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH)₂ D₃ induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH)₂D₃-mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH)₂ D₃ opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH)₂ D₃ may prevent lung cancer progression in a molecularly defined subset of NSCLC patients.