Inhibition of Protein Synthesis Induced by CHK1 Inhibitors Discriminates Sensitive from Resistant Cancer Cells

2021 ◽  
Author(s):  
John W. Hinds ◽  
Jennifer P. Ditano ◽  
Alan Eastman
Keyword(s):  
Protein Synthesis ◽  
Cancer Cells ◽  
Inhibition Of Protein Synthesis

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 Increased Susceptibility of Breast Cancer Cells to Stress Mediated Inhibition of Protein Synthesis

2008 ◽  
Vol 68 (12) ◽  
pp. 4862-4874 ◽  
Author(s):  
Shehla Pervin ◽  
An H. Tran ◽  
Shaghayegh Zekavati ◽  
Jon M. Fukuto ◽  
Rajan Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Inhibition Of Protein Synthesis ◽  
Increased Susceptibility
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