Laryngeal Cancer Cells Metabolize 25-Hydroxyvitamin D and Respond to 24R,25-dihydroxyvitamin D via a Mechanism Dependent on Estrogen Receptor Levels.

Studies have evaluated vitamin D's therapeutic potential in estrogen-responsive cancers, with conflicting findings. We have shown that the proliferation of breast cancer cells is regulated by 24R,25-dihydroxyvitamin D (24R,25(OH)D) depending on estrogen receptor alpha 66 (ERα66) expression, suggesting that this could also be the case for estrogen-sensitive laryngeal cancer cells. Accordingly, we examined levels of ERα isoforms in ERα66-positive UM-SCC-12 and ERα66-negative UM-SCC-11A cells and their response to 24R,25(OH)D. 24R,25(OH)D stimulated proliferation, increased the expression of metastatic markers, and inhibited apoptosis in UM-SCC-12 cells while having the opposite effect in UM-SCC-11A cells. To evaluate if vitamin metabolites could act via autocrine/paracrine mechanisms, we assessed the expression, protein levels, and activity of vitamin D hydroxylases CYP24A1 and CYP27B1. Both cell types expressed both mRNAs; but the levels of the enzymes and their activities were differentially regulated by estrogen. ERα66-negative UM-SCC-11A cells produced more 24,25(OH)D than UM-SCC-12 cells, but comparable levels of 1,25(OH)D when treated with 25(OH)D These results suggest that the regulation of vitamin D metabolism in laryngeal cancer cells is modulated by ERα66 expression, and support a role for 24R,25(OH)D as an autocrine/paracrine regulator of laryngeal cancer. The local metabolism of 25(OH)D should be considered when determining the potential of vitamin D in laryngeal cancer.