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- Title
Laryngeal Cancer Cells Metabolize 25-Hydroxyvitamin D 3 and Respond to 24R,25-dihydroxyvitamin D 3 via a Mechanism Dependent on Estrogen Receptor Levels.
- Authors
Dennis, Cydney D.; Dillon, Jonathan T.; Patel, Prit H.; Cohen, David J.; Halquist, Matthew S.; Pearcy, Adam C.; Boyan, Barbara D.; Schwartz, Zvi
- Abstract
Simple Summary: Vitamin D supplementation's effectiveness in reducing cancer is widely debated. The controversy may be explained by differences in 25(OH)D3 metabolism. Previous studies showed that breast cancer cells produce vitamin D3 metabolites locally, and their ability to regulate tumorigenesis is related to the presence of estrogen receptor alpha 66 (ERα66). The present study examined this process in another estrogen-dependent cancer, laryngeal cancer. This study evaluated the effects of the active vitamin D3 metabolite 24R,25(OH)2D3 on cell growth, whether these cells can produce their own secreted vitamin D3 metabolites, and whether this ability is related to the presence or absence of ERα66. To address these questions, ERα-positive (UM-SCC-12) and ERα-negative (UM-SCC-11A) laryngeal cancer cell lines were examined for the presence of ERα66; the enzymes responsible for metabolizing 25(OH)D3 (CYP24A1 and CYP27B1); the local production of 24,25(OH)2D3 and 1,25(OH)2D3; and the effect of 24R,25(OH)2D3 on cell growth and markers of metastasis. The results showed that laryngeal cancer cells express CYP24A1 and CYP27B1, produce 24,25(OH)2D3, and respond differently to 24R,25(OH)2D3, in correlation with ERα66 levels. These findings suggest that tumor cells locally produce vitamin D metabolites to regulate their growth, which must be considered when recommending vitamin D supplementation. Studies have evaluated vitamin D3'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 D3 (24R,25(OH)2D3) 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)2D3. 24R,25(OH)2D3 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 D3 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)2D3 than UM-SCC-12 cells, but comparable levels of 1,25(OH)2D3 when treated with 25(OH)D3 These results suggest that the regulation of vitamin D3 metabolism in laryngeal cancer cells is modulated by ERα66 expression, and support a role for 24R,25(OH)2D3 as an autocrine/paracrine regulator of laryngeal cancer. The local metabolism of 25(OH)D3 should be considered when determining the potential of vitamin D3 in laryngeal cancer.
- Subjects
VITAMIN D metabolism; NEOPLASTIC cell transformation; RESEARCH funding; LARYNGEAL tumors; CELL proliferation; APOPTOSIS; HEAD &; neck cancer; ESTROGEN; ENZYMES; TUMOR markers; CELL lines; METABOLITES; ESTROGEN receptors; RNA; GENE expression; DISEASE progression
- Publication
Cancers, 2024, Vol 16, Issue 9, p1635
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16091635