Laryngeal Cancer Cells Metabolize 25-Hydroxyvitamin D3 and Respond to 24R,25-dihydroxyvitamin D3 via a Mechanism Dependent on Estrogen Receptor Levels

Cydney D Dennis; Jonathan T Dillon; Prit H Patel; David J Cohen; Matthew S Halquist; Adam C Pearcy; Barbara D Boyan; Zvi Schwartz

doi:10.3390/cancers16091635

Laryngeal Cancer Cells Metabolize 25-Hydroxyvitamin D₃ and Respond to 24R,25-dihydroxyvitamin D₃ via a Mechanism Dependent on Estrogen Receptor Levels

Cancers (Basel). 2024 Apr 24;16(9):1635. doi: 10.3390/cancers16091635.

Authors

Cydney D Dennis¹, Jonathan T Dillon¹, Prit H Patel¹, David J Cohen¹, Matthew S Halquist^{2

3}, Adam C Pearcy², Barbara D Boyan^{1

4}, Zvi Schwartz^{1

5}

Affiliations

¹ Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA.
² Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA.
³ Bioanalytical Core Laboratory, Central Virginia Drug Abuse Research Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁴ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁵ Department of Periodontics, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Abstract

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.

Keywords: estrogen receptor; head and neck cancer; local production; vitamin D metabolism.

Grants and funding

This research was awarded the Ron Horst Presentation Award from the 2022 Vitamin D Workshop in Austin, Texas. This research is also supported by the Joan and Morgan Massey Foundation, Richmond, VA, USA.