Background: Few effective medical treatment options are available for adrenocortical carcinoma (ACC). Intensive efforts are therefore going on for exploring novel pathways and treatment targets.
Objective: To perform a proteomic and pathway analysis on a 9-cisRA (9-cis retinoic acid) and mitotane-treated ACC xenograft model.
Methods: 43 male SCID mice xenografted with NCI-H295R cells were treated in four groups (i. control, ii. 5 mg/kg 9-cisRA, iii. 200 mg/kg mitotane, iv. 9-cisRA + mitotane) for 28 days. Protein isolates from three tumor samples from each group were subjected to SDS-PAGE separation followed by LC-MSMS analysis. After the normalization and statistical analysis of the data, one protein was chosen for validation by Western-blotting. For pathway-analysis David 6.7 was used.
Results: 47 significant protein-level changes were found in the 9-cisRA+mitotane group relative to the control. By considering literature data, the SET protein was validated as being significantly down-regulated in the combined treatment group relative to the untreated control. SET protein was weakly expressed in human ACC samples, but not in benign adenomas, parallelling our xenograft data. Pathway analysis indicated the potential interaction of significantly affected proteins with p53- and Wnt-pathways that are known to be relevant in ACC pathogenesis. Processes linked to ribosome and proteasome were also identified as potentially affected.
Conclusions: The SET protein appears to be a novel player in ACC biology, but its pathogenic relevance along with the other pathways need to be confirmed in further studies. 9-cisRA might represent a novel treatment modality in ACC that could be used as an additive to mitotane.