The eEF2 Kinase Confers Resistance to Nutrient Deprivation by Blocking Translation Elongation

Leprivier, Gabriel; Remke, Marc; Rotblat, Barak; Dubuc, Adrian M.; Mateo, Abigail Rachele F.; Kool, Marcel; Agnihotri, Sameer; El-Naggar, Amal M.; Yu, Bin; Somasekharan, Syam Prakash; Faubert, Brandon; Bridon, Gaëlle; Tognon, Cristina E.; Mathers, Joan; Thomas, Ryan M.; Li, Amy; Barokas, Adi; Kwok, Brian; Bowden, Mary; Smith, Stephanie; Wu, Xiaochong; Korshunov, Andrey; Hielscher, Thomas; Northcott, Paul A.; Galpin, Jason D.; Ahern, Christopher A.; Wang, Ye; McCabe, Martin G.; Collins, V. Peter; Jones, Russell G.; Pollak, Michael; Delattre, Olivier; Gleave, Martin; Jan, Eric; Pfister, Stefan M.; Proud, Christopher G.; Derry, W. Brent; Taylor, Michael D.; Sorensen, Poul H.

doi:10.1016/j.cell.2013.04.055

Cited by 365 publications

(421 citation statements)

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“…A wide range of alterations in gene expression have been identified in cancers. Eukaryotic initiation factor is reported in some cancer (Nakamura et al, 2009;Chen et al, 2011;Leprivier et al, 2013) but the mechanisms of eEF2 in lung cancer was not clear. Our results show that eEF2 is highly expressed in non-small cell lung cancer (NSCLC).…”

Section: Discussionmentioning

confidence: 99%

Clinical Value of Eukaryotic Elongation Factor 2 (eEF2) in Non-small Cell Lung Cancer Patients

Sun

Dong²,

Lü³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Section: Discussionmentioning

confidence: 99%

Clinical Value of Eukaryotic Elongation Factor 2 (eEF2) in Non-small Cell Lung Cancer Patients

Sun

Dong²,

Lü³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…eEF-2K expression (mRNA) correlates poorly with outcome for at least three types of cancer, including hormone-sensitive breast cancer and glioblastoma (10 -17), and has been shown to promote the survival of various cancer cell lines in response to a range of stresses (13,14,(17)(18)(19)(20). Most notably, it has been shown to mediate an adaptive response to severe nutrient deprivation in transformed cells, suggesting that it confers protection to the hypoxic and nutrient-deprived environment of the tumor (17).…”

Section: Eef-2kmentioning

confidence: 99%

The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation

Tavares¹,

Ferguson

Giles

et al. 2014

Journal of Biological Chemistry

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Background: Eukaryotic elongation factor 2 kinase (eEF-2K) regulates protein translation elongation rates. Results: eEF-2K activation involves a two-step process of calmodulin binding and rapid Thr-348 autophosphorylation. Conclusion: Activation of eEF-2K involves two distinct allosteric steps, both of which potentially induce a conformational change. Significance: This mechanism provides a framework for understanding how eEF-2K integrates inputs from multiple upstream signaling pathways.

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“…eEF2 phosphorylation is regulated by a single Ca 2+ /calmodulin-dependent kinase, eukaryotic elongation factor 2 kinase (CAMKIII/eEF2K). eEF2K is inhibited by mTORC1-p70 S6K and ERK-p90 RSK through eEF2K-Ser 366 phosphorylation and activated by Ca 2+ /calmodulin and AMPK (29,30). BHPI increases cytosol Ca 2+ and activates AMPK, but inhibiting AMPK did not inhibit eEF2 phosphorylation (SI Appendix, Fig.…”

Section: Bhpi Rapidly Depletes Intracellular Atp Stores and Activatesmentioning

confidence: 99%

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

Andruska¹,

Zheng²,

Yang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

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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 (IP 3 ), which opens EnR IP 3 R calcium channels, rapidly depleting EnR Ca 2+ 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 Ca 2+ levels, but the open EnR IP 3 R 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 therapyresistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.estrogen receptor | drug discovery | breast cancer | unfolded protein response | ovarian cancer E strogens, acting via estrogen receptor α (ERα), stimulate tumor growth (1-3). Approximately 70% of breast cancers are ERα-positive and most deaths due to breast cancer are in patients with ERα + tumors (2, 4). Endocrine therapy using aromatase inhibitors to block estrogen production, or tamoxifen and other competitor antiestrogens, often results in selection and outgrowth of resistant tumors. Although 30-70% of epithelial ovarian tumors are ERα-positive (1), endocrine therapy is largely ineffective (5-7). After several cycles of chemotherapy, tumors recur as resistant ovarian cancer (5), and most patients die within 5 years (8).Noncompetitive ERα inhibitors targeting this unmet therapeutic need, including DIBA, TPBM, TPSF, and LRH-1 inhibitors that reduce ERα levels, show limited specificity, require high concentrations (>5 μM), and usually have not advanced through preclinical development (9-12). These noncompetitive ERα inhibitors and competitor antiestrogens are primarily cytostatic and act by preventing estrogen-ERα action; therefore, they are largely ineffective in therapy-resistant ERα containing cancer cells that no longer requi...

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The eEF2 Kinase Confers Resistance to Nutrient Deprivation by Blocking Translation Elongation

Cited by 365 publications

References 50 publications

Clinical Value of Eukaryotic Elongation Factor 2 (eEF2) in Non-small Cell Lung Cancer Patients

Clinical Value of Eukaryotic Elongation Factor 2 (eEF2) in Non-small Cell Lung Cancer Patients

The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation

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

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