CoChat
Sign Up
Cited by 34PI3K/AKT/mTOR signaling in cancerAutophagy in Disease and TherapyMetabolism, Diabetes, and Cancer

Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy

Open access
Guan, Yidi, Jiang, Shilong, Ye, Wenling, Ren, Xingcong, Wang, Xinluan, Zhang, Yi, Yin, Mingzhu, Wang, Kuansong +4 more·2020·Cell Death & Disease
DOI 10.1038/s41419-020-03153-xPMC PMC7642277
Open this paper in CoChat — free accountOpen PDF

Abstract

Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41419-020-03153-x

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 43

  1. [1]Cohen A Hall MN An amino acid shuffle activates mTORC1 Cell 2009 136 399 400 10.1016/j.cell.2009.01.021 19203575 · DOI
  2. [2]Saxton RA Sabatini DM mTOR signaling in growth, metabolism, and disease Cell 2017 168 960 976 10.1016/j.cell.2017.02.004 28283069 PMC5394987 · DOI · Paper page
  3. [3]Sarbassov DD Guertin DA Ali SM Sabatini DM Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex Science 2005 307 1098 1101 10.1126/science.1106148 15718470 · DOI · Paper page
  4. [4]Xia Y A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin Sci. Transl. Med. 2014 6 263ra161 10.1126/scitranslmed.3010382 PMC4326221 25411474 · DOI
  5. [5]Bjornsti MA Houghton PJ The TOR pathway: a target for cancer therapy Nat. Rev. Cancer 2004 4 335 348 10.1038/nrc1362 15122205 · DOI
  6. [6]Li J Kim SG Blenis J Rapamycin: one drug, many effects Cell Metab. 2014 19 373 379 10.1016/j.cmet.2014.01.001 24508508 PMC3972801 · DOI · Paper page
  7. [7]Kida Y Efficacy and safety of sirolimus in lymphangioleiomyomatosis N. Engl. J. Med. 2011 365 271 10.1056/NEJMc1106358 21774718 · DOI
  8. [8]Chung J Kuo CJ Crabtree GR Blenis J Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases Cell 1992 69 1227 1236 10.1016/0092-8674(92)90643-Q 1377606 · DOI
  9. [9]Tabernero J Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors J. Clin. Oncol. 2008 26 1603 1610 10.1200/JCO.2007.14.5482 18332469 · DOI
  10. [10]Sun SY Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition Cancer Res. 2005 65 7052 7058 10.1158/0008-5472.CAN-05-0917 16103051 · DOI
  11. [11]Rodrik-Outmezguine VS mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling Cancer discovery 2011 1 248 259 10.1158/2159-8290.CD-11-0085 22140653 PMC3227125 · DOI · Paper page
  12. [12]Fiskus W Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells Mol. Cancer Ther. 2013 12 577 588 10.1158/1535-7163.MCT-12-0862 23445613 · DOI
  13. [13]Kim LC Cook RS Chen J mTORC1 and mTORC2 in cancer and the tumor microenvironment Oncogene 2017 36 2191 2201 10.1038/onc.2016.363 27748764 PMC5393956 · DOI
  14. [14]Cheng Y Ren X Hait WN Yang JM Therapeutic targeting of autophagy in disease: biology and pharmacology Pharmacol. Rev. 2013 65 1162 1197 10.1124/pr.112.007120 23943849 PMC3799234 · DOI
  15. [15]Rangwala R Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma Autophagy 2014 10 1391 1402 10.4161/auto.29119 24991838 PMC4203516 · DOI
  16. [16]Leprivier G The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation Cell 2013 153 1064 1079 10.1016/j.cell.2013.04.055 23706743 PMC4395874 · DOI
  17. [17]Hait WN Wu H Jin S Yang JM Elongation factor-2 kinase: its role in protein synthesis and autophagy Autophagy 2006 2 294 296 10.4161/auto.2857 16921268 · DOI
  18. [18]Cheng Y Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells Autophagy 2013 9 208 219 10.4161/auto.22801 23182879 PMC3552884 · DOI
  19. [19]Cheng Y eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206 Cancer Res. 2011 71 2654 2663 10.1158/0008-5472.CAN-10-2889 21307130 PMC3210447 · DOI
  20. [20]Cheng Y eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis Oncogene 2016 35 6293 6308 10.1038/onc.2016.166 27181208 · DOI
  21. [21]Browne GJ Proud CG A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin Mol. Cell. Biol. 2004 24 2986 2997 10.1128/MCB.24.7.2986-2997.2004 15024086 PMC371112 · DOI
  22. [22]Wang X Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase EMBO J. 2001 20 4370 4379 10.1093/emboj/20.16.4370 11500364 PMC125559 · DOI
  23. [23]King TD Song L Jope RS AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3 Biochem. Pharmacol. 2006 71 1637 1647 10.1016/j.bcp.2006.03.005 16620785 PMC1618797 · DOI
  24. [25]Lv G Lx2-32c, a novel semi-synthetic taxane, exerts antitumor activity against prostate cancer cells in vitro and in vivo Acta Pharmaceutica Sinica. B 2017 7 52 58 10.1016/j.apsb.2016.06.005 28119808 PMC5237719 · DOI
  25. [26]Wang Q Edupuganti R Tavares CD Dalby KN Ren P Using docking and alchemical free energy approach to determine the binding mechanism of eEF2K inhibitors and prioritizing the compound synthesis Front. Mol. Biosci. 2015 2 9 10.3389/fmolb.2015.00009 25988177 PMC4429643 · DOI
  26. [27]Xiao T Liu R Proud CG Wang MW A high-throughput screening assay for eukaryotic elongation factor 2 kinase inhibitors Acta Pharmaceutica Sinica. B 2016 6 557 563 10.1016/j.apsb.2016.04.002 27818922 PMC5071636 · DOI
  27. [28]Edupuganti R Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors Bioorg. med. chem. 2014 22 4910 4916 10.1016/j.bmc.2014.06.050 25047940 PMC6473179 · DOI
  28. [29]Guo Y Design, synthesis and structure-activity relationship of a focused library of beta-phenylalanine derivatives as novel eEF2K inhibitors with apoptosis-inducing mechanisms in breast cancer Eur. J. Med. Chem. 2018 143 402 418 10.1016/j.ejmech.2017.11.065 29202403 · DOI
  29. [30]Fan QW A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma Cancer Cell 2006 9 341 349 10.1016/j.ccr.2006.03.029 16697955 PMC2925230 · DOI
  30. [31]Basu B First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014 Clin. Cancer Res. 2015 21 3412 3419 10.1158/1078-0432.CCR-14-2422 25805799 PMC4512239 · DOI
  31. [32]Thoreen CC An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1 J. Biol. Chem. 2009 284 8023 8032 10.1074/jbc.M900301200 19150980 PMC2658096 · DOI · Paper page
  32. [33]Kim KY Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation Cancer Res. 2009 69 4018 4026 10.1158/0008-5472.CAN-08-2641 19366811 · DOI
  33. [34]Tzatsos A Tsichlis PN Energy depletion inhibits phosphatidylinositol 3-kinase/Akt signaling and induces apoptosis via AMP-activated protein kinase-dependent phosphorylation of IRS-1 at Ser-794 J. Biol. Chem. 2007 282 18069 18082 10.1074/jbc.M610101200 17459875 · DOI
  34. [35]Xie CM Liu XY Sham KW Lai JM Cheng CH Silencing of EEF2K (eukaryotic elongation factor-2 kinase) reveals AMPK-ULK1-dependent autophagy in colon cancer cells Autophagy 2014 10 1495 1508 10.4161/auto.29164 24955726 PMC4206530 · DOI
  35. [36]Degenhardt K Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis Cancer Cell 2006 10 51 64 10.1016/j.ccr.2006.06.001 16843265 PMC2857533 · DOI
  36. [38]Kim J Kundu M Viollet B Guan KL AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 Nat. Cell Biol. 2011 13 132 141 10.1038/ncb2152 21258367 PMC3987946 · DOI · Paper page
  37. [39]Zeng Q Inhibition of REDD1 sensitizes bladder urothelial carcinoma to paclitaxel by inhibiting autophagy Clin. Cancer Res. 2018 24 445 459 10.1158/1078-0432.CCR-17-0419 29084921 · DOI
  38. [41]Py BF Boyce M Yuan J A critical role of eEF-2K in mediating autophagy in response to multiple cellular stresses Autophagy 2009 5 393 396 10.4161/auto.5.3.7762 19221463 PMC2756538 · DOI
  39. [42]Arora S Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines Cancer Res. 2003 63 6894 6899 14583488
  40. [43]Chen Z 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor J. Biol. Chem. 2011 286 43951 43958 10.1074/jbc.M111.301291 22020937 PMC3243513 · DOI
  41. [44]Enriquez CAG Espiritu AI Pasco PMD Efficacy and tolerability of mitoxantrone for neuromyelitis optica spectrum disorder: a systematic review J. Neuroimmunol. 2019 332 126 134 10.1016/j.jneuroim.2019.04.007 31005713 · DOI
  42. [45]Evison BJ Sleebs BE Watson KG Phillips DR Cutts SM Mitoxantrone, more than just another topoisomerase II poison Med. Res. Rev. 2016 36 248 299 10.1002/med.21364 26286294 · DOI
  43. [46]Tang M Can intracellular drug delivery using hyaluronic acid functionalised pH-sensitive liposomes overcome gemcitabine resistance in pancreatic cancer? J. Control. Release 2019 305 89 100 10.1016/j.jconrel.2019.05.018 31096017 · DOI

Cited by

Sorted by citations

Authors
Guan, Y., Jiang, S., Ye, W., Ren, X., Wang, X., Zhang, Y., Yin, M., Wang, K., Tao, Y., Yang, J., Cao, D., & Cheng, Y.
Affiliations
  • Second Xiangya Hospital of Central South University (CN)
  • Central South University (CN)
  • University of Kentucky (US)
  • Chinese Academy of Sciences (CN)
  • Soochow University (CN)
  • Xiangya Hospital Central South University (CN)
Corresponding author
  • Cao, Dongsheng
  • Cheng, Yan
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2020-11-03
Volume
11
Issue
11
Pages
948-948
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-020-03153-x
PMC
PMC7642277
OpenAlex
W3097066549
Cited by
34
References
3
Citations by year
2026: 1 · 2025: 8 · 2024: 8 · 2023: 7 · 2022: 4 · 2021: 6
FWCI
1.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81422051, 81972480)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
mitoxantrone, rapalogs, mTOR inhibitors, breast cancer, drug resistance, Akt signaling, autophagy, combination therapy, synergistic cytotoxicity, structure-based virtual screening
MeSH terms
Animals, Antineoplastic Agents, Autophagy, Breast Neoplasms, Drug Therapy, Combination, Female, Humans, Mice, Nude, Mitoxantrone, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Apoptosis, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Elongation Factor 2 Kinase, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review