TY  - JOUR
AU  - Zhang, G.
AU  - Yanamala, N.
AU  - Lathrop, KL.
AU  - Zhang, L.
AU  - Klein-Seetharaman, J.
AU  - Srinivas, H.
TI  - Ligand-independent antiapoptotic function of estrogen receptor-beta in lung cancer cells
JO  - Molecular endocrinology
VL  - 24
SN  - 0888-8809
CY  - Bethesda, Md.
PB  - Endocrine Society
M1  - PreJuSER-13100
SP  - 1737 - 1747
PY  - 2010
N1  - 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.
AB  - 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.
KW  - Apoptosis: drug effects
KW  - Carcinoma, Non-Small-Cell Lung: metabolism
KW  - Carcinoma, Non-Small-Cell Lung: pathology
KW  - Cell Line, Tumor
KW  - Cell Survival: drug effects
KW  - Cisplatin: pharmacology
KW  - Estrogen Receptor beta: chemistry
KW  - Estrogen Receptor beta: metabolism
KW  - Gene Knockdown Techniques
KW  - Humans
KW  - Immunoprecipitation
KW  - Inhibitory Concentration 50
KW  - Ligands
KW  - Lung Neoplasms: metabolism
KW  - Lung Neoplasms: pathology
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Models, Biological
KW  - Models, Molecular
KW  - Protein Binding: drug effects
KW  - Protein Structure, Tertiary
KW  - Protein Transport: drug effects
KW  - RNA, Small Interfering: metabolism
KW  - bcl-Associated Death Protein: chemistry
KW  - bcl-Associated Death Protein: metabolism
KW  - bcl-X Protein: metabolism
KW  - Estrogen Receptor beta (NLM Chemicals)
KW  - Ligands (NLM Chemicals)
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - bcl-Associated Death Protein (NLM Chemicals)
KW  - bcl-X Protein (NLM Chemicals)
KW  - Cisplatin (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:20660297
C2  - pmc:PMC2940472
UR  - <Go to ISI:>//WOS:000281387300005
DO  - DOI:10.1210/me.2010-0125
UR  - https://juser.fz-juelich.de/record/13100
ER  -