The aim of this study was to investigate the metabolic changes that occur in
adrenocortical cancer (ACC) cells in response to the modulation of
Estrogen Related Receptor (ERR)α expression and the impact on ACC progression. Proteomics analysis and metabolic profiling highlighted an important role for ERRα in the regulation of ACC metabolism. Stable ERRα overexpression in H295R cells promoted a better mitochondrial fitness and prompted toward a more aggressive phenotype characterized by higher
Vimentin expression, enhanced cell migration and spheroids formation. By contrast, a decrease in ERRα
protein levels, by molecular (
short hairpin RNA) and pharmacological (inverse agonist
XCT790) approaches modified the energetic status toward a low energy profile and reduced
Vimentin expression and ability to form spheroids.
XCT790 produced similar effects on two additional ACC cell lines, SW13 and
mitotane-resistant MUC-1 cells. Our findings show that ERRα is able to modulate the metabolic profile of ACC cells, and its inhibition can strongly prevent the growth of
mitotane-resistant ACC cells and the progression of ACC cell models to a highly migratory phenotype. Consequently, ERRα can be considered an important target for the design of new therapeutic strategies to fight ACC progression.