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  • 24R ,25( OH ) 2D3 regulates tumorigenesis in estrogen sensitive laryngeal cancer cells via membrane‐associated receptor complexes in ER + and ER− cells
Title: 24R ,25( OH ) 2D3 regulates tumorigenesis in estrogen sensitive laryngeal cancer cells via membrane‐associated receptor complexes in ER + and ER− cells
Abstract This study examined the effects of 24R,25‐dihydroxyvitamin D3(24R,25(OH)2D3) in estrogen‐responsive laryngeal cancer tumorigenesis in vivo, the mechanisms involved, and whether the ability of the tumor cells to produce 24R,25(OH)2D3locally is estrogen‐dependent. Estrogen receptor alpha‐66 positive (ER+) UM‐SCC‐12 cells and ER− UM‐SCC‐11A cells responded differently to 24R,25(OH)2D3in vivo; 24R,25(OH)2D3enhanced tumorigenesis in ER+ tumors but inhibited tumorigenesis in ER− tumors. Treatment with 17β‐estradiol (E2) for 24 h reduced levels of CYP24A1 protein but increased 24R,25(OH)2D3production in ER+ cells; treatment with E2for 9 min reduced CYP24A1 at 24 h and reduced 24R,25(OH)2D3production in ER− cells. These findings suggest the involvement of E2receptor(s) in addition to ERα66. To investigate if 24R,25(OH)2D3can act locally, ER+ and ER− cells were treated with 24R,25(OH)2D3after inhibiting putative 24R,25(OH)2D3receptors, and the cells were assessed for effects on DNA synthesis (proliferation) and p53 production (apoptosis). Specific inhibitors were used to assess downstream secondary messenger signaling pathways and requirements for palmitoylation and caveolae in both cell lines. The results show that 24R,25(OH)2D3binds to a complex of receptors, including TLCD3B2, VDR, and protein disulfide‐isomerase A3 (PDIA3) in ER+ UM‐SCC‐12 cells. The mechanism requires palmitoylation, and PLD, PI3K, and LPAR are involved. The anti‐tumorigenic effects of 24R,25(OH)2D3in ER− UM‐SCC‐11A cells involve a membrane‐receptor complex consisting of VDR, PDIA3, and ROR2 within caveolae to activate a yet‐to‐be‐elucidated downstream signaling cascade. This work demonstrates a driving mechanism for the therapeutic agent 24R,25(OH)2D3that may be used for laryngeal cancer patients.  more » « less
Award ID(s):
2316003
PAR ID:
10645375
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  
Publisher / Repository:
John Wiley & Sons Ltd
Date Published:
Journal Name:
International Journal of Cancer
ISSN:
0020-7136
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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