Background: The medical treatment options of adrenocortical cancer are limited. In our previous meta-analysis of adrenocortical tumor genomics data, adrenocortical cancer was found to be associated with reduced retinoic acid production and retinoid X receptor-mediated signaling.
Objective: To study the potential antitumoral effects of 9-cis-retinoic acid (9-cisRA) on the adrenocortical cancer cell line NCI-H295R and in a xenograft model.
Methods: Cell proliferation (flow cytometry), hormone secretion (cortisol, dehydroepiandrosterone, aldosterone) and gene expression (microarray) have been studied in the NCI-H295R cell line. A complex bioinformatics approach involving pathway and network analysis and comparison to previously published microarray studies have been performed. Selected genes were validated by real-time qRT-PCR. Athymic nude mice xenografted with NCI-H295R were used in a small pilot in vivo xenograft model for the study of 9-cisRA on tumor growth.
Results: 9-cisRA significantly decreased cell viability and steroid hormone secretion in a concentration- and time-dependent manner in the NCI-H295R cell line. Four major molecular pathways have been identified by the analysis of gene expression data. Ten genes involved in: i) steroid hormone secretion (HSD3B1, HSD3B2), ii) retinoic acid signaling (ABCA1, ABCG1, HMGCR), iii) cell cycle damage (GADD45A, CCNE2, UHRF1) and the iv) immune response (MAP2K6, IL1R2) were successfully validated. 9-cisRA appears to directly regulate cell cycle by network analysis. In the in vivo xenograft model 9-cisRA reduced tumor growth, as well.
Conclusions: 9-cisRA might represent a promising new candidate in the treatment of hormone-secreting adrenal tumors and adrenocortical cancer.