Ligand-Independent Antiapoptotic Function of Estrogen Receptor-β in Lung Cancer Cells
| Autor: | Harish Srinivas, Naveena Yanamala, Kira L. Lathrop, Judith Klein-Seetharaman, GuangFeng Zhang, Lin Zhang |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Cell type Lung Neoplasms Cell Survival bcl-X Protein Estrogen receptor Apoptosis Mitochondrion Biology Ligands Models Biological Article Small hairpin RNA Inhibitory Concentration 50 Endocrinology Downregulation and upregulation Carcinoma Non-Small-Cell Lung Cell Line Tumor Estrogen Receptor beta Humans Immunoprecipitation RNA Small Interfering Molecular Biology Estrogen receptor beta Gene knockdown General Medicine Mitochondria Protein Structure Tertiary Cell biology Protein Transport Gene Knockdown Techniques Cancer research bcl-Associated Death Protein Cisplatin Protein Binding |
| Zdroj: | Molecular Endocrinology. 24:1737-1747 |
| ISSN: | 1944-9917 0888-8809 |
| DOI: | 10.1210/me.2010-0125 |
| Popis: | Recent studies have demonstrated the presence of estrogen receptor (ER)β 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 ERβ in non-small-cell lung cancer (NSCLC) cells. Down-regulation of ERβ 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 ERβ-knockdown cells was observed irrespective of estrogen treatment, suggesting a ligand-independent role of ERβ in regulating the intrinsic apoptotic pathway. Further, ERβ 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 ERβ, and the BH3 domain of Bad were involved in these interactions. Further investigations revealed that ERβ inhibited Bad function by disrupting Bad-Bcl-XL and Bad-Bcl-2 interactions. Reintroduction of ERβ in the mitochondria of ERβ knockdown cells reversed their sensitivity to cisplatin. Overall, our results demonstrate a ligand-independent role of ERβ in regulating apoptosis, revealing a novel function for ERβ in the mitochondria. |
| Databáze: | OpenAIRE |
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