Journal Article

PreJuSER-13100

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Ligand-independent antiapoptotic function of estrogen receptor-beta in lung cancer cells

Zhang, G. ; Yanamala, N. ; Lathrop, K. ; Zhang, L. ; Klein-Seetharaman, J.FZJ* ; Srinivas, H.

2010
Endocrine Society Bethesda, Md.

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Please use a persistent id in citations: doi:10.1210/me.2010-0125

Abstract: Recent studies have demonstrated the presence of estrogen receptor (ER)beta in the mitochondria in various cell types and tissues, but the exact function of this localization remains unclear. In this study, we have examined the function of mitochondrial ERbeta in non-small-cell lung cancer (NSCLC) cells. Down-regulation of ERbeta by short hairpin RNA constructs sensitized NSCLC cells to various apoptosis-inducing agents such as cisplatin, taxol, and etoposide. The increased growth inhibition and induction of apoptosis in ERbeta-knockdown cells was observed irrespective of estrogen treatment, suggesting a ligand-independent role of ERbeta in regulating the intrinsic apoptotic pathway. Further, ERbeta from the mitochondrial fraction physically interacted with the proapoptotic protein Bad, in a ligand-independent manner. Glutathione-S-transferase pull-down assays and molecular modeling studies revealed that the DNA-binding domain and hinge region of ERbeta, and the BH3 domain of Bad were involved in these interactions. Further investigations revealed that ERbeta inhibited Bad function by disrupting Bad-Bcl-X(L) and Bad-Bcl-2 interactions. Reintroduction of ERbeta in the mitochondria of ERbeta knockdown cells reversed their sensitivity to cisplatin. Overall, our results demonstrate a ligand-independent role of ERbeta in regulating apoptosis, revealing a novel function for ERbeta in the mitochondria.

Keyword(s): Apoptosis: drug effects (MeSH) ; Carcinoma, Non-Small-Cell Lung: metabolism (MeSH) ; Carcinoma, Non-Small-Cell Lung: pathology (MeSH) ; Cell Line, Tumor (MeSH) ; Cell Survival: drug effects (MeSH) ; Cisplatin: pharmacology (MeSH) ; Estrogen Receptor beta: chemistry (MeSH) ; Estrogen Receptor beta: metabolism (MeSH) ; Gene Knockdown Techniques (MeSH) ; Humans (MeSH) ; Immunoprecipitation (MeSH) ; Inhibitory Concentration 50 (MeSH) ; Ligands (MeSH) ; Lung Neoplasms: metabolism (MeSH) ; Lung Neoplasms: pathology (MeSH) ; Mitochondria: drug effects (MeSH) ; Mitochondria: metabolism (MeSH) ; Models, Biological (MeSH) ; Models, Molecular (MeSH) ; Protein Binding: drug effects (MeSH) ; Protein Structure, Tertiary (MeSH) ; Protein Transport: drug effects (MeSH) ; RNA, Small Interfering: metabolism (MeSH) ; bcl-Associated Death Protein: chemistry (MeSH) ; bcl-Associated Death Protein: metabolism (MeSH) ; bcl-X Protein: metabolism (MeSH) ; Estrogen Receptor beta ; Ligands ; RNA, Small Interfering ; bcl-Associated Death Protein ; bcl-X Protein ; Cisplatin ; J

Note: This work was supported by the Career Development Award from the University of Pittsburgh Specialized Program of Research Excellence (SPORE) in Lung Cancer and by the Core Grant for Vision Research EY08098.

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Contributing Institute(s):

1. Molekulare Biophysik (ISB-2)

Research Program(s):

1. BioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung (P45)

Appears in the scientific report 2010

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