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

Author(s)

Bueno, Ana Carolina ; More, Candy Bellido ; Marrero-Gutierrez, Junier ; Silva, Danillo C. de Almeida E. ; Leal, Leticia Ferro ; Montaldi, Ana Paula ; Ramalho, Fernando Silva ; Nicoliello Vencio, Ricardo Zorzetto ; de Castro, Margaret ; Antonini, Sonir Roberto R.

• Document type: Journal article
• Source: Molecular and Cellular Endocrinology; v. 558, p. 14-pg., 2022-09-02.

Abstract

Objective: To evaluate the therapeutic potential of vitamin D receptor (VDR) signaling in adrenocortical carcinoma (ACC) cells. Methods: We evaluated VDR's methylation pattern in H295R ACC cells, and investigated the effects of calcitriol and seocalcitol treatments on adrenocortical tumorigenesis. Results: 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. Conclusions: 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. (AU)

• FAPESP's process: 21/04368-9 - Physiopathological and molecular mechanisms of tumorigenesis: Genomic scale sequencing platform based approach (NGS - Next-generation sequencing)
• Grantee: Danillo Cunha de Almeida e Silva
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 15/19663-5 - Investigation of the Molecular basis of adrenocortical tumors and search for new therapeutic targets.
• Grantee: Sonir Roberto Rauber Antonini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/17737-7 - Role of YAP1 oncogene in tumorigenesis and metastasis processes, and its inhibition in pediatric adrenocortical tumors by verteporfin
• Grantee: Candy Christie Bellido More
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 22/04883-3 - Identification of molecular variations involved in pituitary tumorigenesis based on exomic sequencing and transcriptome
• Grantee: Junier Marrero Gutiérrez
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/03989-6 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS)
• Grantee: Margaret de Castro
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/00860-6 - Uncovering pathophysiological and molecular mechanisms involvedin tumorigenesis by platforms for next-generation sequencing (NGS)
• Grantee: Ana Carolina Bueno de Queiroz Arruda
• Support Opportunities: Scholarships in Brazil - Post-Doctoral