Estrogen related receptor α (ERRα) a promising target for the therapy of adrenocortical carcinoma (ACC)

Oncotarget. 2015 Sep 22;6(28):25135-48. doi: 10.18632/oncotarget.4722.

Abstract

The pathogenesis of the adrenocortical cancer (ACC) involves integration of molecular signals and the interplay of different downstream pathways (i.e. IGFII/IGF1R, β-catenin, Wnt, ESR1). This tumor is characterized by limited therapeutic options and unsuccessful treatments. A useful strategy to develop an effective therapy for ACC is to identify a common downstream target of these multiple pathways. A good candidate could be the transcription factor estrogen-related receptor alpha (ERRα) because of its ability to regulate energy metabolism, mitochondrial biogenesis and signalings related to cancer progression. In this study we tested the effect of ERRα inverse agonist, XCT790, on the proliferation of H295R adrenocortical cancer cell line. Results from in vitro and in vivo experiments showed that XCT790 reduced H295R cell growth. The inhibitory effect was associated with impaired cell cycle progression which was not followed by any apoptotic event. Instead, incomplete autophagy and cell death by a necrotic processes, as a consequence of the cell energy failure, induced by pharmacological reduction of ERRα was evidenced. Our results indicate that therapeutic strategies targeting key factors such as ERRα that control the activity and signaling of bioenergetics processes in high-energy demanding tumors could represent an innovative/alternative therapy for the treatment of ACC.

Keywords: ATP depletion; ERRα; adrenocortical cancer; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Neoplasms / drug therapy*
  • Adrenal Cortex Neoplasms / genetics
  • Adrenal Cortex Neoplasms / metabolism
  • Adrenal Cortex Neoplasms / pathology
  • Adrenocortical Carcinoma / drug therapy*
  • Adrenocortical Carcinoma / genetics
  • Adrenocortical Carcinoma / metabolism
  • Adrenocortical Carcinoma / pathology
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Autophagy / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Partial Agonism
  • Energy Metabolism / drug effects
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molecular Targeted Therapy
  • Necrosis
  • Nitriles / pharmacology*
  • Receptors, Estrogen / drug effects*
  • Receptors, Estrogen / metabolism
  • Signal Transduction / drug effects
  • Thiazoles / pharmacology*
  • Time Factors
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Hormonal
  • ERRalpha estrogen-related receptor
  • Nitriles
  • Receptors, Estrogen
  • Thiazoles
  • XCT790