Reactive oxygen species induce phosphorylation of serine 118 and 167 on estrogen receptor alpha

Abstract

Estrogen receptor alpha (ERalpha) is a well-known target for signaling pathways originating from growth factor receptors. Reactive oxygen species (ROS) can induce activation of extracellular response kinase 1/2 (Erk1/2) and protein kinase B (Akt). Both kinases have been implicated in the phosphorylation of serine 118 and serine 167 on ERalpha, respectively. This activity may lead either to ligand-independent activation of ERalpha or down-regulation of ERalpha and may contribute to development of the resistance to endocrine therapy. Treatment of MCF-7 human breast cancer cells with glucose oxidase (GO, 0.1 un/ml) induced transient phosphorylation of serine 118 and serine 167. The increase in expression of p-ser118-ERalpha was 355 +/- 98% (mean +/- SD) and of p-ser167-ERalpha was 632 +/- 355%. These effects were enhanced in Her2 over-expressing MCF7 cells. ERalpha expression declined to 63 +/- 20% within the first 90 min of treatment and was below 10% 24 h later. ROS induced phosphorylation of ERalpha resulted in decreased expression of pS2 and progesterone receptor. Activation of Erk1/2 and Akt was transient with highest levels of Erk1/2 being 595 +/- 143% and p-Akt 311 +/- 125%. Inhibition of Erk1/2 by U0126 (10 microM) decreased p-ser118-ERalpha by 51.7 +/- 8.5% and decreased p-ser167-ERalpha by 41.9 +/- 16.9% whereas inhibition of Akt by LY294002 (20 microM) and wortmannin (500 nM) or by siRNA knock-down, had no effect on p-ser167-ERalpha expression. Our data show for the first time that ROS can induce post-translational modifications of ERalpha at serine 118 and serine 167, and may lead to ERalpha down-regulation in human breast cancer cells. Both the phosphorylation and consequent down-regulation of ERalpha may be a mechanism associated with development of endocrine therapy resistance.

Glyoxalase I inhibition induces apoptosis in irradiated MCF-7 cells via a novel mechanism involving Hsp27, p53 and NF-κB

“…In the attempt to reveal the molecular mechanism underlying ROS-dependent GI mRNA downregulation, ER α and ERK1/2 signalling were studied. In fact, it has been shown that ROS can induce post-translational Erk1/2-dependent phosphorylation of ER α at serine 118, leading to ER α downregulation in MCF-7 (Weitsman et al , 2009). Moreover, we previously found that oestrogens positively modulated GI transcript levels in MCF-7 cell, possibly through the interaction of their receptors with degenerated ERE motives, identified in GI promoter by bioinformatics methods (Rulli et al , 2006).…”

Butein suppresses breast cancer growth by reducing a production of intracellular reactive oxygen species

“…As ROS and AKT are involved in breast cancer metastasis [37,47,48], environmental forces for tumor development and metastasis may modulate ROS and AKT in cancer cells, vice versa . Meanwhile, ROS appears to force endocrine therapy resistance as well as tumorigenicity in ER + breast cancer, as glucose oxidase-mediated ROS induction led to the phosphorylation and downregulation of ERα in MCF-7 [42,49]. Likewise, ROS appears to regulate both the growth and invasiveness of TNBC cells [50,51].…”

Gestational Hypoxia Increases Reactive Oxygen Species and Inhibits Steroid Hormone–Mediated Upregulation of Ca 2+ -Activated K + Channel Function in Uterine Arteries

“…ROS has been shown to induce post-translational modifications of ER-α, leading to ER-α downregulation in human breast cancer cells. 30 Scavenging free radicals by NAC removed inhibitory effects of ROS, allowing steroid hormones to upregulate K Ca channel function. Correspondingly, BK Ca channel activity in uterine arterial smooth muscle cells was also restored by NAC with the hormonal treatment.…”