Vitamin D receptor activation is a feasible therapeutic target to impair adrenocortical tumorigenesis

• Published in: Molecular and cellular endocrinology 2022-12, Vol.558, p.111757, Article 111757
• Main Authors: Bueno, Ana Carolina, More, Candy Bellido, Marrero-Gutiérrez, Junier, de Almeida e Silva, Danillo C., Leal, Leticia Ferro, Montaldi, Ana Paula, Ramalho, Fernando Silva, Vêncio, Ricardo Zorzetto Nicoliello, de Castro, Margaret, Antonini, Sonir Roberto R.
• Format: Article
• Language: English
• Subjects: Adrenal Cortex Neoplasms - drug therapy; Adrenal Cortex Neoplasms - genetics; Adrenocortical Carcinoma - drug therapy; Adrenocortical Carcinoma - genetics; Adrenocortical tumor; Calcitriol - pharmacology; Carcinogenesis - genetics; Catenins - pharmacology; Cell Line, Tumor; Cell Transformation, Neoplastic; H295R cells; Hormones - pharmacology; Humans; Receptors, Calcitriol - genetics; Target therapy; Vitamin D - pharmacology; Vitamin D receptor; Wnt Signaling Pathway
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2022.111757

To evaluate the therapeutic potential of vitamin D receptor (VDR) signaling in adrenocortical carcinoma (ACC) cells. We evaluated VDR's methylation pattern in H295R ACC cells, and investigated the effects of calcitriol and seocalcitol treatments on adrenocortical tumorigenesis. VDR was hypermethylated and underexpressed in basal H295R cells. Treatments with calcitriol and seocalcitol restored VDR signaling, resulted in antiproliferative effects, and impaired Wnt/B-catenin signaling. RNAseq of treated cells demonstrated VDR activation on steroid hormones biosynthesis and Rap1 signaling, among others. In vivo, seocalcitol constrained the growth of H295R xenografts and reduced autonomous tumor steroid secretion without hypercalcemia-associated side effects. H295R cells present VDR hypermethylation, which can be responsible for its underexpression and signaling inactivation under basal conditions. VDR signaling promoted antiproliferative effects in vitro and in vivo, suggesting that it may be a potential therapeutic target for ACC and a valuable tool for patient's clinical management. •Resembling adrenocortical carcinomas, VDR DNA is hypermethylated in H295R cells.•VDR is underexpressed and inactive in H295R cells under basal conditions.•Vitamin D treatment restores VDR signaling in H295R cells and impairs tumorigenesis.•Cell-active VDR transcriptome landscape reinforces its influence in steroid synthesis and reveals novel pathways associated with ACC.•Seocalcitol inhibits H295R xenograft autonomous steroid secretion.