Ligand-Independent Antiapoptotic Function of Estrogen Receptor-β in Lung Cancer Cells

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.

The presence of Estrogen Receptor β modulates the response of breast cancer cells to therapeutic agents

“…Results obtained here indicate that the silencing of ER␤ triggered a better response to CDDP in T47D cells, showing an increment in apoptosis and autophagy, as well as in ROS production. These results agree with other authors who revealed that the down-regulation of ER␤ sensitized lung cancer cells to various apoptosis-inducing agents such as cisplatin or taxol (Zhang et al, 2010). Additionally, in 2013 Pereira et al showed that the induction of ROS in colon and breast cancer cells sensitized them to CDDP-induced apoptosis (Pereira et al, 2013).…”

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

“…FLAG-tagged ER␤ was purchased from Addgene (plasmid 35562, deposited by Harish Srinivas) (23). myc-tagged ER␣, ER␣(1-270), ER␣(300 -595), ER␣(180 -595), and ER␣(180 -353) were described previously (12).…”

Tumor suppressor p53 and estrogen receptors in nuclear–mitochondrial communication

“…However, there are models where ERβ expression has been shown to be associated with proliferation (Jensen et al, 2001; Skliris et al, 2006) contradicting the proposed tumor suppressor role of ERβ. Notably, increased growth inhibition and induction of apoptosis was observed in ERβ-knockdown non-small cell lung cancer (NSCLC) cells in a ligand-independent manner (Zhang et al, 2010a). Moreover, ERβ from the mitochondrial fraction physically interacted with the proapoptotic protein Bad: the DNA-binding domain along with the hinge domain of ERβ and the BH3 domain of Bad are necessary for this interaction.…”

“…Their study also demonstrates the presence of both ERs within the mitochondria of MCF7 cells and enhanced ERα and ERβ mitochondrial localization in MCF-7 cells after E2 treatment. In contrast, Studies conducted by Srinivas and co-workers on mitochondrial ERβ role in non-small-cell lung cancer (NSCLC) cells have demonstrated a ligand-independent role of ERβ in regulating apoptosis, establishing a novel function for ERβ in the mitochondria (Zhang et al, 2010b). Although the localization of ERs to the mitochondria has been demonstrated by various techniques, the issue still remains unsettled (Klinge, 2008; Psarra and Sekeris, 2008).…”