scholarly journals Estrogen receptor-α signaling and localization regulates autophagy and unfolded protein response activation in ER+ breast cancer

2014 ◽  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Unfolded Protein Response ◽  
Estrogen Receptor Α ◽  
Unfolded Protein ◽  
Protein Response ◽  
Response Activation

scholarly journals Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

2015 ◽  
Vol 112 (15) ◽  
pp. 4737-4742 ◽  
Author(s):  
Neal D. Andruska ◽  
Xiaobin Zheng ◽  
Xujuan Yang ◽  
Chengjian Mao ◽  
Mathew M. Cherian ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Protein Synthesis ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Tumor Regression ◽  
Estrogen Receptor Α ◽  
Unfolded Protein ◽  
Inhibition Of Protein Synthesis ◽  
The Unfolded Protein Response ◽  
Protein Response

Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen–ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen–ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα+ cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP3), which opens EnR IP3R calcium channels, rapidly depleting EnR Ca2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca2+ levels, but the open EnR IP3R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI’s novel mode of action, high potency, and effectiveness in therapy-resistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.

TXNIP links anticipatory unfolded protein response to estrogen reprogramming glucose metabolism in breast cancer cells

Endocrinology ◽  
2021 ◽  
Author(s):  
Yuanzhong Wang ◽  
Shiuan Chen
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Breast Cancer Cells ◽  
Unfolded Protein ◽  
Protein Response

Abstract Estrogen and estrogen receptor (ER) play a fundamental role in breast cancer. To adapt the rapid proliferation of ER+ breast cancer cells, estrogen increases glucose uptake and reprograms glucose metabolism. Meanwhile, estrogen/ER activates the anticipatory unfolded protein response (UPR) preparing cancer cells for the increased protein production required for subsequent cell proliferation. Here, we report that thioredoxin-interacting protein (TXNIP) is an important regulator of glucose metabolism in ER+ breast cancer cells, and estrogen/ER increases glucose uptake and reprograms glucose metabolism via activating anticipatory unfolded protein response (UPR) and subsequently repressing TXNIP expression. By using two widely used ER+ breast cancer cell lines MCF7 and T47D, we showed that MCF7 cells express high TXNIP levels and exhibit mitochondrial oxidative phosphorylation (OXPHOS) phenotype, while T47D cells express low TXNIP levels and display aerobic glycolysis (Warburg effect) phenotype. Knockdown of TXNIP promoted glucose uptake and Warburg effect, while forced overexpression of TXNIP inhibited glucose uptake and Warburg effect. We further showed that estrogen represses TXNIP expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of TXNIP expression and estrogen-induced cell proliferation. Together, our study suggests that TXNIP is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells, and links anticipatory UPR to estrogen reprogramming glucose metabolism.

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