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Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer

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Abstract

The currently available medical treatment options of adrenocortical cancer (ACC) are limited. In our previous meta-analysis of adrenocortical tumor genomics data, ACC was associated with reduced retinoic acid production and retinoid X receptor-mediated signaling. Our objective has been to study the potential antitumoral effects of 9-cis retinoic acid (9-cisRA) on the ACC cell line NCI-H295R and in a xenograft model. Cell proliferation, hormone secretion, and gene expression have been studied in the NCI-H295R cell line. A complex bioinformatics approach involving pathway and network analysis has been performed. Selected genes have been validated by real-time qRT-PCR. Athymic nude mice xenografted with NCI-H295R have been used in a pilot in vivo xenograft model. 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 have been successfully validated involved in: (1) steroid hormone secretion (HSD3B1, HSD3B2), (2) retinoic acid signaling (ABCA1, ABCG1, HMGCR), (3) cell-cycle damage (GADD45A, CCNE2, UHRF1), and the (4) immune response (MAP2K6, IL1R2). 9-cisRA appears to directly regulate the cell cycle by network analysis. 9-cisRA also reduced tumor growth in the in vivo xenograft model. In conclusion, 9-cisRA might represent a promising new candidate in the treatment of hormone-secreting adrenal tumors and adrenocortical cancer.

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Acknowledgments

This study has been funded by the Hungarian Scientific Research Fund (OTKA K100295).

Author information

Authors and Affiliations

  1. 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Szentkirályi Str. 46, Budapest, 1088, Hungary

    Diana Rita Szabó, Adrienn Zsippai, István Marczell, Zoltán Nagy, Vivien Varga, Károly Rácz & Peter Igaz

  2. 1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, Üllői Str. 26, Budapest, 1088, Hungary

    Kornélia Baghy & Ilona Kovalszky

  3. Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Szentkirályi Str. 46, Budapest, 1088, Hungary

    Peter M. Szabó & Attila Patócs

  4. Department of Genetics, Cell- and Immunobiology, Faculty of Medicine, Semmelweis University, Nagyvárad Sq. 4, Budapest, 1089, Hungary

    Katalin Éder, Sára Tóth, Edit I. Buzás & András Falus

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  1. Diana Rita Szabó
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Correspondence to Peter Igaz.

Electronic supplementary material

Below is the link to the electronic supplementary material.

18_2013_1408_MOESM1_ESM.tif

Supplementary Figure 1 Association of cell viability (A) and DHEA concentrations (B) with treatment periods (TIFF 698 kb)

18_2013_1408_MOESM2_ESM.tif

Supplementary Figure 2 Hierarchical clustering of gene expression following flag (100 % present in at least one group) and fold change (fold change > 2) filtering of microarray results. Hierarchical clustering was performed by GeneSpring software 10.1. NCI-H295R cells were incubated with ethanol (control groups) and with 9-cisRA for 24 h in three different concentration. The rows represent the individual genes. The gene expression levels are displayed in each independent sample. Both genes and the groups were clustered by centroid linkage method calculating with Euclidean distance. Overexpression is indicated with red, underexpression is represented with blue (TIFF 962 kb)

18_2013_1408_MOESM3_ESM.tif

Supplementary Figure 3 Pathways with related gene expression patterns involved in cells-cycle regulation (aryl hydrocarbon receptor (AHR) signaling, cyclins and cell-cycle regulation and the estrogen-mediated S-phase entry pathways) after 9-cisRA treatment in NCI-H295R cells (left sides of circular symbols representing gene expression) and investigated microarray studies in ACC (right sides of circular symbols representing gene expression) (TIFF 822 kb)

18_2013_1408_MOESM4_ESM.tif

Supplementary Figure 4 Pathways with related gene expression patterns involved in the immune regulation after 9-cisRA treatment in NCI-H295R cells (left sides of circular symbols representing gene expression) and investigated microarray studies in ACC (right sides of circular symbols representing gene expression) (TIFF 1023 kb)

18_2013_1408_MOESM5_ESM.tif

Supplementary Figure 5 Gene expression network with altered gene expression patterns and feed-forward loop (FFL) motifs after 9-cisRA treatment in NCI-H295R cells (TIFF 765 kb)

18_2013_1408_MOESM6_ESM.tif

Supplementary Figure 6 Correlation between gene expression changes and 9-cisRA concentrations for eight genes by Spearman correlation. A: CCNE2, B: GADD45A, C: HSD3B1, D: HSD3B2, E: IL1R2. F: MAP2K6, G: HMGCR, H: UHRF1 (p value < 0.05, R2 > 0.7) (TIFF 702 kb)

18_2013_1408_MOESM7_ESM.xlsx

Supplementary Table 1 List of 699, 2,320, and 2,303 significantly differentially expressed genes between control and the 2.5 × 10−5M, 5 × 10−5M and 7.5 × 10−5M 9-cisRA-treated cell cultures, respectively at 24 h (p < 0.05) (XLSX 171 kb)

18_2013_1408_MOESM8_ESM.xlsx

Supplementary Table 2 List of 246 detected genes that were common in at least two comparisons of control and 9-cisRA-treated groups and in at least two former ACA and ACC microarray studies (p < 0.05) (XLSX 31 kb)

18_2013_1408_MOESM9_ESM.xlsx

Supplementary Table 3 List of 21 significant canonical pathways in at least two comparisons of control and 9-cisRA-treated groups and in at least two ACA and ACC microarray studies (p < 0.05) (XLSX 20 kb)

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Szabó, D.R., Baghy, K., Szabó, P.M. et al. Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer. Cell. Mol. Life Sci. 71, 917–932 (2014). https://doi.org/10.1007/s00018-013-1408-z

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  • DOI: https://doi.org/10.1007/s00018-013-1408-z

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