Avena Paola, De Luca Arianna, Chimento Adele, Nocito Marta Claudia, Sculco Sara, La Padula Davide, Zavaglia Lucia, Giulietti Matteo, Hantel Constanze, Sirianni Rosa, Casaburi Ivan, Pezzi Vincenzo
Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy.
Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy.
Cancers (Basel). 2022 Aug 11;14(16):3885. doi: 10.3390/cancers14163885.
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.
本研究旨在探究肾上腺皮质癌（ACC）细胞中因雌激素相关受体（ERR）α表达调控而发生的代谢变化及其对ACC进展的影响。蛋白质组学分析和代谢谱分析突出了ERRα在ACC代谢调控中的重要作用。H295R细胞中ERRα的稳定过表达促进了更好的线粒体适应性，并促使其向更具侵袭性的表型转变，其特征为波形蛋白表达更高、细胞迁移增强和球体形成。相比之下，通过分子（短发夹RNA）和药理学（反向激动剂XCT790）方法降低ERRα蛋白水平，会使能量状态朝着低能量状态改变，并降低波形蛋白表达和球体形成能力。XCT790对另外两种ACC细胞系SW13和米托坦耐药的MUC-1细胞产生了类似的作用。我们的研究结果表明，ERRα能够调节ACC细胞的代谢谱，抑制ERRα可有力地阻止米托坦耐药的ACC细胞生长以及ACC细胞模型向高迁移表型的进展。因此，ERRα可被视为对抗ACC进展的新治疗策略设计的重要靶点。
