Functional Estrogen Receptors in the Mitochondria of Breast Cancer Cells

Pedram, Ali; Razandi, Mahnaz; Wallace, Douglas C.; Levin, Ellis R.

doi:10.1091/mbc.e05-11-1013

Cited by 235 publications

(227 citation statements)

References 59 publications

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“…Interestingly, estrogen enhanced MnSOD activity in both female and male brains, while testosterone and DHT had no effect. This alteration in MnSOD activity by estrogen is in agreement with previous studies in vascular tissue demonstrating increased MnSOD activity after in vitro or in vivo estrogen treatment (Pedram et al, 2006;Strehlow et al, 2003). Thus, in our study, the ability of estrogen to increase MnSOD activity represents one mechanism by which estrogen may reduce brain mitochondrial oxidative stress.…”

Section: Discussionsupporting

confidence: 93%

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Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

et al. 2007

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Mitochondria are a major source of reactive oxygen species (ROS) and oxidative stress, key contributors to aging and neurodegenerative disorders. We report that gonadal hormones influence brain mitochondrial ROS production in both females and males. Initial experiments showed that estrogen decreases mitochondrial superoxide production in a receptor-mediated manner, as measured by MitoSOX fluorescence in differentiated PC-12 cells. We then assessed in vivo effects of gonadal hormones on brain mitochondrial oxidative stress in female and male rats. Brain mitochondria were isolated to measure a functional indicator of ROS, i.e., activity of the ROS-sensitive mitochondrial enzyme, aconitase. Gonadectomy of both males and females caused a decrease in aconitase activity, suggesting endogenous gonadal hormones influence mitochondrial ROS production in the brain. In vivo treatment of gonadectomized animals with testosterone or dihydrotestosterone (DHT) had no effect, but estrogen replacement significantly increased aconitase activity in brain mitochondria from both female and male rats. This indicates estrogen decreases brain mitochondrial ROS production in vivo. Sex hormone treatments did not affect protein levels of brain mitochondrial uncoupling proteins (UCP-2, 4, and 5). However, estrogen did increase the activity, but not the levels, of manganese superoxide dismutase (MnSOD), the mitochondrial enzyme that catalyzes superoxide radical breakdown, in brain mitochondria from both female and male rats. Thus, in contrast to the lack of effect of androgens on mitochondrial ROS, estrogen suppression of mitochondrial oxidative stress may influence neurological disease incidence and progression in both females and males.

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Section: Discussionsupporting

confidence: 93%

“…MnSOD protein levels are, however, only one index of superoxide metabolism; evidence suggests MnSOD activity may be regulated as well (Azevedo et al, 2001;Pedram et al, 2006;Strehlow et al, 2003). Interestingly, estrogen enhanced MnSOD activity in both female and male brains, while testosterone and DHT had no effect.…”

Section: Discussionmentioning

confidence: 99%

Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

et al. 2007

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“…PKC␦ has been shown to promote resistance to tamoxifen, ␥-irradiation, retinoic acid, and TRAIL (8,9,33,34). On the other hand, apoptosis induced by UV light is mediated via PKC␦ (14,15). Here, we report that down-regulation of PKC␦ per se leads to apoptosis in the MDA-MB-231 cell line.…”

Section: Discussionmentioning

confidence: 65%

“…PKC␦ has also been shown to promote both metastasis (10 -12) and proliferation (13) of murine mammary cancer and epithelial cells. On the other hand, PKC␦ has also been shown to be crucial for induction of apoptosis in breast cancer cells (14,15).…”

mentioning

confidence: 99%

Protein Kinase Cδ Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway

Lønne

Masoumi

Lennartsson

et al. 2009

Journal of Biological Chemistry

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Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase C␦ (PKC␦) is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. Here, we report for the first time that down-regulation of PKC␦ per se leads to apoptosis of MDA-MB-231 cells. Inhibition of MEK1/2 by either PD98059 or U0126 suppressed the induction of apoptosis of PKC␦-depleted MDA-MB-231 cells but did not support survival of MCF-7 or MDA-MB-468 cells. Basal ERK1/2 phosphorylation was substantially higher in MDA-MB-231 cells than in the other cell lines. PKC␦ depletion led to even higher ERK1/2 phosphorylation levels and also to lower expression levels of the ERK1/2 phosphatase MKP3. Depletion of MKP3 led to apoptosis and higher levels of ERK1/2 phosphorylation, suggesting that this may be a mechanism mediating the effect of PKC␦ down-regulation. However, PKC␦ silencing also induced increased MEK1/2 phosphorylation, indicating that PKC␦ regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKC␦ silencing led to increased levels of the E3 ubiquitin ligase Nedd4, which is a potential regulator of MKP3, because down-regulation led to increased MKP3 levels. Our results highlight PKC␦ as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.

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“…It is interesting to note that mitochondrial dysfunction has been linked to a wide range of degenerative and metabolic diseases, cancer, and aging (Wallace et al 2010). Pedram et al (2006) have shown that in the mitochondria of MCF-7 breast cancer cells and endothelial cells there are high-affi nity estrogen receptors, which impact mitochondrial functions and control the survival of the tumor cells. PGRMC2 (progesterone receptor membrane component 2) also known as steroid receptor protein DG6 and progesterone membrane binding protein (PMBP), is a member of non-classical progesterone signaling molecules (membrane progestin receptors) and a potential downstream eff ector of FOXM1 transcription factor, which plays important roles in tumorigenesis and tumor metastasis in multiple human carcinomas as tumor suppressor, migration inhibitor, and regulator of cytochrome P450 proteins (Petersen et al 2013;Wendler and Wehling 2013;Ye et al 2015).…”

mentioning

confidence: 99%

Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

et al. 2017

Endocrine Regulations

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Objective. Th e aim of the present study was to examine the eff ect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1), which is a central mediator of the unfolded protein response on the expression of genes encoded estrogen related proteins (NRIP1/RIP140, TRIM16/EBBP, ESRRA/NR3B1, FAM162A/E2IG5, PGRMC2/PMBP, and SLC39A6/LIV-1) and their hypoxic regulation in U87 glioma cells for evaluation of their possible signifi cance in the control of glioma cells proliferation.Methods. Th e expression of NRIP1, EBBP, ESRRA, E2IG5, PGRMC2, and SLC39A6 genes in U87 glioma cells, transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia, was studied by a quantitative polymerase chain reaction.Results. Inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 signaling enzyme function up-regulates the expression of EBBP, E2IG5, PGRMC2, and SLC39A6 genes is in U87 glioma cells in comparison with the control glioma cells, with more signifi cant changes for E2IG5 and PGRMC2 genes. At the same time, the expression of NRIP1 and ESRRA genes is strongly down-regulated in glioma cells upon inhibition of IRE1. We also showed that hypoxia increases the expression of E2IG5, PGRMC2, and EBBP genes and decreases NRIP1 and ESRRA genes expression in control glioma cells. Furthermore, the inhibition of IRE1 in U87 glioma cells decreases the eff ect of hypoxia on the expression of E2IG5 and PGRMC2 genes, eliminates hypoxic regulation of NRIP1 gene, and enhances the sensitivity of ESRRA gene to hypoxic condition. Furthermore, the expression of SLC39A6 gene is resistant to hypoxia in both the glioma cells with and without IRE1 signaling enzyme function. Conclusions.Results of this investigation demonstrate that inhibition of IRE1 signaling enzyme function aff ects the expression of NRIP1, EBBP, ESRRA, E2IG5, PGRMC2, and SLC39A6 genes in U87 glioma cells in gene specifi c manner and these changes possibly contribute to the suppression of the cell proliferation. Most of these genes are regulated by hypoxia and preferentially through IRE1 signaling pathway of endoplasmic reticulum stress.

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Functional Estrogen Receptors in the Mitochondria of Breast Cancer Cells

Cited by 235 publications

References 59 publications

Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

Protein Kinase Cδ Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway

Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

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