scholarly journals Targeting multidrug-resistant ovarian cancer through estrogen receptor α dependent ATP depletion caused by hyperactivation of the unfolded protein response

Oncotarget ◽  
2016 ◽  
Vol 9 (19) ◽  
pp. 14741-14753 ◽  
Author(s):  
Xiaobin Zheng ◽  
Neal Andruska ◽  
Michael J. Lambrecht ◽  
Sisi He ◽  
Amadeo Parissenti ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Estrogen Receptor ◽  
Unfolded Protein Response ◽  
Estrogen Receptor Α ◽  
Multidrug Resistant ◽  
Atp Depletion ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

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.

scholarly journals ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Richard H Chapple ◽  
Tianyuan Hu ◽  
Yu-Jung Tseng ◽  
Lu Liu ◽  
Ayumi Kitano ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Estrogen Receptor Α ◽  
Protein Homeostasis ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Systemic Mechanism ◽  
Unfolded Protein ◽  
Proteotoxic Stress ◽  
The Unfolded Protein Response ◽  
Protein Response

Activation of the unfolded protein response (UPR) sustains protein homeostasis (proteostasis) and plays a fundamental role in tissue maintenance and longevity of organisms. Long-range control of UPR activation has been demonstrated in invertebrates, but such mechanisms in mammals remain elusive. Here, we show that the female sex hormone estrogen regulates the UPR in hematopoietic stem cells (HSCs). Estrogen treatment increases the capacity of HSCs to regenerate the hematopoietic system upon transplantation and accelerates regeneration after irradiation. We found that estrogen signals through estrogen receptor α (ERα) expressed in hematopoietic cells to activate the protective Ire1α-Xbp1 branch of the UPR. Further, ERα-mediated activation of the Ire1α-Xbp1 pathway confers HSCs with resistance against proteotoxic stress and promotes regeneration. Our findings reveal a systemic mechanism through which HSC function is augmented for hematopoietic regeneration.

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