Vitamin D3 Inhibits Wnt/β-Catenin and mTOR Signaling Pathways in Human Uterine Fibroid Cells.

Vitamin D3 Inhibits Wnt/β-Catenin and mTOR Signaling Pathways in Human Uterine Fibroid Cells.

J Clin Endocrinol Metab. 2016 Jan 28;:jc20153555

Authors: Al-Hendy A, Diamond MP, Boyer TG, Halder SK

Abstract
CONTEXT: Somatic mutations in the Med12 gene are known to activate Wnt/β-catenin signaling in human uterine fibroids (UFs).
OBJECTIVE: To examine the role of vitamin D3 in modulation of Wnt/β-catenin and mTOR signaling in human UF cells.
DESIGN: Immortalized human UF cells (HuLM) and human primary UF (PUF) cells were treated with increasing concentrations of vitamin D3 and thereafter analyzed using western blots and immunocytochemistry.
MAIN OUTCOME MEASURES: Wnt/β-catenin, and mTOR signaling proteins in cultured HuLM and PUF cells.
RESULTS: UF tumors with Med12 somatic mutations showed upregulation of Wnt4 and β-catenin as compared with adjacent myometrium. Vitamin D3 administration reduced the levels of Wnt4 and β-catenin in both HuLM and PUF cells. Vitamin D3 also reduced the expression/activation of mTOR signaling in both cell types. In contrast, vitamin D3 induced the expression of DDIT4 (an inhibitor of mTOR) and tuberous sclerosis genes (TSC1/2) in a concentration-dependent manner in HuLM cells. Furthermore, we observed a concentration-dependent reduction of Wisp1 (Wnt induced signaling protein 1) and FEN 1 proteins in HuLM cells. Additionally, abrogation of vitamin D receptor (VDR) expression (by silencing) in normal myometrial cells induces Wnt4/β-catenin as well as prompts a fibrotic process including an increase in cell proliferation and increased ECM production. Together, these results suggest that vitamin D3 functions as an inhibitor of Wnt4/β-catenin and mTOR signaling pathways, which may play major roles in fibroid pathogenesis.
CONCLUSION: Vitamin D3 may have utility as a novel long-term therapeutic and/or preventive option for uterine fibroids.

PMID: 26820714 [PubMed - as supplied by publisher]

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1PEAAhI
via IFTTT