Estrogen Receptor β as a Mitochondrial Vulnerability Factor

Yang, Shao Hua; Sarkar, Sourav; Liu, Ran; Perez, Evelyn; Wang, Xiaofei; Yi, Wen; Yan, Lianh Jun; Simpkins, James W.

doi:10.1074/jbc.m808246200

Cited by 80 publications

(64 citation statements)

References 62 publications

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“…These results suggested that ER␤ was involved in the regulation of ATP production and mitochondrial oxidative phosphorylation in macrophages. This hypothesis was supported by the literature indicating that ER␤ is involved in mitochondrial membrane potential maintenance and mitochondrial vulnerability (29). Importantly, relocation of the ER␤ after separating from ATPase requires further study.…”

Section: Figure 5 Estrogen Exerts Its Inhibitory Effects Via Er␤ Butsupporting

confidence: 66%

“…7) initiated by E2 as a mechanism to explain its suppressive effects on tumor-associated alternatively activated macrophage cells. ER␤ mainly located in the mitochondria (29), and it combined with the ATPase under the stimulus of IL-4. Therefore, ER␤ was involved in the regulation of ATP production and mitochondrial oxidative phosphorylation in macrophages after IL-4 treatment.…”

Section: Estrogen Damages the Interaction Of Er␤ And Atpase In Il-4-smentioning

confidence: 99%

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Estrogen Represses Hepatocellular Carcinoma (HCC) Growth via Inhibiting Alternative Activation of Tumor-associated Macrophages (TAMs)

Yang

et al. 2012

Journal of Biological Chemistry

114

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Background: Hepatocarcinoma cancer (HCC) occurs more often in men than in women, and little is known about its underlying molecular mechanisms. Results: We identify that 17␤-estradiol (E2) could suppress tumor growth via regulating the polarization of macrophages. Conclusion: Estrogen functions as a suppressor for macrophage alternative activation. Significance: These studies introduce a novel mechanism for suppressing male-predominant HCC.

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Section: Figure 5 Estrogen Exerts Its Inhibitory Effects Via Er␤ Butsupporting

confidence: 66%

Section: Estrogen Damages the Interaction Of Er␤ And Atpase In Il-4-smentioning

confidence: 99%

Estrogen Represses Hepatocellular Carcinoma (HCC) Growth via Inhibiting Alternative Activation of Tumor-associated Macrophages (TAMs)

Yang

et al. 2012

Journal of Biological Chemistry

114

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“…uniporter by mitochondrial estrogen receptors [42]. The role of ERb in the inhibition of apoptosis is further supported by the lowering of resting mitochondrial membrane potential following mitochondrial ERb knockdown [43]. Chemotherapy resistance may be further enhanced by the rapid nongenomic effects of extranuclear ERb on cell proliferation [31].…”

Section: Discussionmentioning

confidence: 98%

Nuclear and cytoplasmic expressions of ERβ1 and ERβ2 are predictive of response to therapy and alters prognosis in familial breast cancers

Yan

Rayoo²,

Takano

et al. 2010

Breast Cancer Res Treat

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Estrogen receptor (ER) α has been studied extensively in familial breast cancers but there are limited data on ERβ and its isoforms. This is an important issue since many BRCA1-associated tumours are "triple negative" and are resistant to conventional and targeted therapies. We performed an immunohistochemical study of pan-ERβ, ERβ1 and ERβ2 in a cohort of 123 familial breast carcinomas (35 BRCA1, 33 BRCA2 and 55 BRCAX) using a cut-off for positivity at 20% (Shaaban et al. in Clin Cancer Res 14:5228-5235, 2008). BRCA1 cancers were more likely to be nuclear ERα negative and nuclear pan-ERβ positive (21/32, 66%) when compared with BRCA2 (2/29, 7%) and BRCAX cancers (11/49, 22%) (both P < 0.001). For survival analysis, expression was also stratified using cut-offs defined by Bates et al. (Breast Cancer Res Treat 111:453-459, 2008) (score out of 7). Cytoplasmic ERβ2 expression correlated with shorter overall survival at 15 years regardless of cut-off used (both P < 0.046) At a cut-off score of 6 out of 7, cytoplasmic ERβ2 expression correlated with a poorer response to chemotherapy in both univariate (P = 0.011) and multivariate analyses including grade, lymph node status and chemotherapy as an interaction variable (P = 0.045, Hazard ratio 1.22, 95% CI 1.004-9.87). A similar trend was seen in a univariate analysis with a cut-off of 20% although this did not reach statistical significance (P = 0.057). Expression of nuclear ERβ1 was associated with a favourable response to endocrine therapy at 15 years regardless of cut-offs employed (both P < 0.025). However, this did not reach statistical significance in a multivariate analysis (P > 0.05). Since a significant proportion of ERα negative familial breast carcinomas are positive for nuclear ERβ1 and cytoplasmic ERβ2, the different ERβ isoforms and their intracellular location may need to be assessed, to identify patients that may benefit from hormonal and chemotherapy.

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“…The enzyme cytochrome c oxidase complex IV (COXIV) plays a critical role in mitochondrial energy generation and it has been demonstrated that E2 can regulate its activity [26,27]. To elucidate if the hormone modulates COXIV activity in C2C12 cells, the myoblasts were treated with E2 or vehicle during different time intervals (1 - 4 h).…”

Section: Resultsmentioning

confidence: 99%

17�-Estradiol Protects Mitochondrial Functions through Extracellular-Signal-Regulated Kinase in C2C12 Muscle Cells

Ronda

Vasconsuelo²,

Boland³

2013

Cell Physiol Biochem

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Background/Aims: We have previously shown that exposure to 17β-estradiol (E2) prior to induction of apoptosis with H₂O₂ protects skeletal muscle cells against oxidative damage. However, the mechanism involved in the protective action of the hormone is poorly understood. In the present study, we focused on the mechanism by which ERK mediates this survival effect in connection with COXIV activity and mitochondrial membrane potential. Methods: Immunocytochemistry, Western blot, cytochrome c oxidase complex IV (COXIV) activity, coimmunoprecipitation and JC-1 dye by flow cytometry were carried out using C2C12 myoblasts as experimental model. Results: E2 is able to activate ERK and then induces its translocation to mitochondria. Using the pharmacological inhibitor of ERK activation U0126 we show that E2, through ERK activation, is able to enhance COXIV activity. Moreover, the hormone increases the interaction between COXIV and ERK. Also, we found that hydrogen peroxide decreases COXIV activity and that preincubation of the cells with E2 prior to induction of apoptosis prevents this effect. In addition, we observe that the estrogen inhibits the collapse of mitochondrial membrane potential induced by H₂O₂, involving ERK and COXIV. Conclusion: Our data demonstrate that E2 promotes ERK activation and translocation to mitochondria preventing the decline in COXIV activity and in turn, alteration of mitochondrial membrane potential by oxidative stress, in C2C12 myoblasts.

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Estrogen Receptor β as a Mitochondrial Vulnerability Factor

Cited by 80 publications

References 62 publications

Estrogen Represses Hepatocellular Carcinoma (HCC) Growth via Inhibiting Alternative Activation of Tumor-associated Macrophages (TAMs)

Estrogen Represses Hepatocellular Carcinoma (HCC) Growth via Inhibiting Alternative Activation of Tumor-associated Macrophages (TAMs)

Nuclear and cytoplasmic expressions of ERβ1 and ERβ2 are predictive of response to therapy and alters prognosis in familial breast cancers

17�-Estradiol Protects Mitochondrial Functions through Extracellular-Signal-Regulated Kinase in C2C12 Muscle Cells

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