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Ligand-independent antiapoptotic function of estrogen receptor-beta in lung cancer cells

Guangfeng Zhang1, Naveena Yanamala, Kira L Lathrop

  • 1Division of Endocrinology and Metabolism, University of Pittsburgh, E1115 Starzl Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA.

Molecular Endocrinology (Baltimore, Md.)
|July 28, 2010
PubMed

Insights

Mitochondrial estrogen receptor beta (ERbeta) plays a key role in non-small-cell lung cancer apoptosis. This ERbeta form regulates apoptosis independently of estrogen, interacting with the Bad protein to control cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Estrogen receptor (ER)beta has been identified in mitochondria, but its function there is largely unknown.
  • Mitochondrial ERbeta's role in cancer, particularly non-small-cell lung cancer (NSCLC), requires further investigation.

Purpose of the Study:

  • To elucidate the function of mitochondrial ERbeta in non-small-cell lung cancer (NSCLC) cells.
  • To determine if ERbeta's role in apoptosis is ligand-dependent or independent.

Main Methods:

  • Short hairpin RNA (shRNA) was used to down-regulate ERbeta in NSCLC cells.
  • Apoptosis-inducing agents (cisplatin, taxol, etoposide) were used to assess cell sensitivity.
  • Glutathione-S-transferase (GST) pull-down assays and molecular modeling were employed to study protein interactions.
  • Reintroduction of ERbeta into knockdown cells was performed to confirm findings.

Main Results:

  • ERbeta knockdown sensitized NSCLC cells to apoptosis-inducing agents, irrespective of estrogen.
  • Mitochondrial ERbeta physically interacted with the proapoptotic protein Bad in a ligand-independent manner.
  • ERbeta inhibited Bad function by disrupting its interactions with Bcl-xL and Bcl-2, thereby regulating apoptosis.

Conclusions:

  • Mitochondrial ERbeta plays a significant role in regulating apoptosis in NSCLC cells.
  • This function is ligand-independent, highlighting a novel role for ERbeta beyond its nuclear functions.
  • ERbeta's interaction with Bad offers a new therapeutic target for NSCLC treatment.

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