ERRα metabolic nuclear receptor controls growth of colon cancer cells

Carcinogenesis. 2013 Oct;34(10):2253-61. doi: 10.1093/carcin/bgt180. Epub 2013 May 29.

Abstract

The estrogen-related receptor alpha (ERRα) is a nuclear receptor that acts primarily as a regulator of metabolic processes, particularly in tissues subjected to high-energy demand. In addition to its control of energy metabolism and mitochondrial biogenesis, ERRα has recently been associated with cancer progression. Notably, increased expression of ERRα has been shown in several cancerous tissues, including breast, ovary and colon. However, additional studies are required to gain insight into the action of ERRα in cancer biology, particularly in non-endocrine-related cancers. Therefore, using a short hairpin RNA-mediated approach, we investigated whether ERRα is required for the rapid growth of colon cancer cells and to maintain their neoplastic metabolic state. Results show that silencing ERRα significantly impaired colon cancer cell proliferation and colony formation in vitro as well as their in vivo tumorigenic capacity. A pronounced delay in G1-to-S cell cycle phase transition was observed in ERRα-depleted cells in association with reduced cyclin-dependent kinase 2 activity and hyperphosphorylated state of the retinoblastoma protein along with disturbed expression of several cell cycle regulators, including p15 and p27. Interestingly, ERRα-depleted HCT116 cells also displayed significant reduction in expression of a large set of key genes to glycolysis, tricarboxylic acid cycle and lipid synthesis. Furthermore, using (14)C isotope tracer analysis, ERRα depletion in colon cancer cells resulted in reduced glucose incorporation and glucose-mediated lipogenesis in these cells. These findings suggest that ERRα coordinates colon cancer cell proliferation and tumorigenic capacity with energy metabolism. Thus, ERRα could represent a promising therapeutic target in colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / genetics
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Energy Metabolism / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Gene Silencing
  • Glucose / metabolism
  • Glycolysis / genetics
  • HCT116 Cells
  • Humans
  • Lipids / biosynthesis
  • Lipogenesis / genetics
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Tumor Stem Cell Assay

Substances

  • Cell Cycle Proteins
  • ERRalpha estrogen-related receptor
  • Lipids
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Glucose