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Eukaryotic elongation factor-2 kinase (eEF2K) signaling in tumor and microenvironment as a novel molecular target

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Abstract

Eukaryotic elongation factor-2 kinase (eEF2K), an atypical member of alpha-kinase family, is highly overexpressed in breast, pancreatic, brain, and lung cancers, and associated with poor survival in patients. eEF2K promotes cell proliferation, survival, and aggressive tumor characteristics, leading to tumor growth and progression. While initial studies indicated that eEF2K acts as a negative regulator of protein synthesis by suppressing peptide elongation phase, later studies demonstrated that it has multiple functions and promotes cell cycle, angiogenesis, migration, and invasion as well as induction of epithelial-mesenchymal transition through induction of integrin β1, SRC/FAK, PI3K/AKT, cyclin D1, VEGF, ZEB1, Snail, and MMP-2. Under stress conditions such as hypoxia and metabolic distress, eEF2K is activated by several signaling pathways and slows down protein synthesis and helping cells to save energy and survive. In vivo therapeutic targeting of eEF2K by genetic methods inhibits tumor growth in various tumor models, validating it as a potential molecular target. Recent studies suggest that eEF2K plays a role in tumor microenvironment cells by monocyte chemoattractant protein-1 (MCP-1) and accumulation of tumor-associated macrophages. Due to its clinical significance and the pivotal role in tumorigenesis and progression, eEF2K is considered as an important therapeutic target in solid tumors. However, currently, there is no specific and potent inhibitor for translation into clinical studies. Here, we aim to systematically review current knowledge regarding eEF2K in tumor biology, microenvironment, and development of eEF2K targeted inhibitors and therapeutics.

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References

  1. Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B (2014a) Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells. Apoptosis 19:241–258

    Article  CAS  PubMed  Google Scholar 

  2. Bayraktar R, Pichler M, Kanlikilicer P, Ivan C, Bayraktar E, Kahraman N, Aslan B, Oguztuzun S, Ulasli M, Arslan A, Calin G, Lopez-Berestein G, Ozpolat B (2017) MicroRNA 603 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting elongation factor 2 kinase. Oncotarget 8:11641–11658

    Article  PubMed  Google Scholar 

  3. Bircan HA, Gurbuz N, Pataer A, Caner A, Kahraman N, Bayraktar E, Bayraktar R, Erdogan MA, Kabil N, Ozpolat B (2018) Elongation factor-2 kinase (eEF-2K) expression is associated with poor patient survival and promotes proliferation, invasion and tumor growth of lung cancer. Lung Cancer 124:31–39

    Article  PubMed  Google Scholar 

  4. Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M, Agnihotri S, El-Naggar A, Yu B, Somasekharan SP, Faubert B, Bridon G, Tognon CE, Mathers J, Thomas R, Li A, Barokas A, Kwok B, Bowden M, Smith S, Wu X, Korshunov A, Hielscher T, Northcott PA, Galpin JD, Ahern CA, Wang Y, McCabe MG, Collins VP, Jones RG, Pollak M, Delattre O, Gleave ME, Jan E, Pfister SM, Proud CG, Derry WB, Taylor MD, Sorensen PH (2013) The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153:1064–1079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhu H, Song H, Chen G, Yang X, Liu J, Ge Y, Lu J, Qin Q, Zhang C, Xu L, Di X, Cai J, Ma J, Zhang S, Sun X (2017) eEF2K promotes progression and radioresistance of esophageal squamous cell carcinoma. Radiother Oncol 124:439–447

    Article  CAS  PubMed  Google Scholar 

  6. Ryazanov AG, Shestakova EA, Natapov P (1988) Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. Nature 334:170–173

    Article  CAS  PubMed  Google Scholar 

  7. Ryazanov AG, Pavur KS, Dorovkov MV (1999) Alpha kinases: a new class of protein kinases with a novel catalytic domain. Curr Biol 9:R43–R45

    Article  CAS  PubMed  Google Scholar 

  8. Kenney JW, Moore CE, Wang X, Proud CG (2014) Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles. Adv Biol Regul 55:15–27

    Article  CAS  PubMed  Google Scholar 

  9. Liu R, Proud CG (2016) Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases. Acta Pharmacol Sin 37:285–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tavernarakis N (2013) Protein synthesis. In: Vijg J, Campisi J, Lithgow G (eds) The molecular and cellular biology of aging. Gerontological Society of America (GSA) Press, Washington DC

    Google Scholar 

  11. Wang X, Xie J, Proud CG (2017) Eukaryotic elongation factor 2 kinase (eEF2K) in cancer. Cancers (Basel) 9:162

    Article  CAS  Google Scholar 

  12. Moore CE, Mikolajek H, Regufe da Mota S, Wang X, Kenney JW, Werner JM, Proud CG (2015) Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia. Mol Cell Biol 35:1788–1804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lazarus MB, Levin RS, Shokat KM (2017) Discovery of new substrates of the elongation factor-2 kinase suggests a broader role in the cellular nutrient response. Cell Signal 29:78–83

    Article  CAS  PubMed  Google Scholar 

  14. Kong M, Ditsworth D, Lindsten T, Thompson CB (2009) Alpha4 is an essential regulator of PP2A phosphatase activity. Mol Cell 36:51–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reid MA, Wang WI, Rosales KR, Welliver MX, Pan M, Kong M (2013) The B. 55alpha subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol Cell 50:200–211

    Article  CAS  PubMed  Google Scholar 

  16. Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hardie DG, Schaffer BE, Brunet A (2015) AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol 26:190–201

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Moore CE, Regufe da Mota S, Mikolajek H, Proud CG (2014) A conserved loop in the catalytic domain of eukaryotic elongation factor 2 kinase plays a key role in its substrate specificity. Mol Cell Biol 34:2294–2307

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Proud CG (2015) Regulation and roles of elongation factor 2 kinase. Biochem Soc Trans 43:328–332

    Article  CAS  PubMed  Google Scholar 

  20. Ryazanov AG (1987) Ca2+/calmodulin-dependent phosphorylation of elongation factor 2. FEBS Lett 214:331–334

    Article  CAS  PubMed  Google Scholar 

  21. Lee K, Alphonse S, Piserchio A, Tavares CD, Giles DH, Wellmann RM, Dalby KN, Ghose R (2016) Structural basis for the recognition of eukaryotic elongation factor 2 kinase by calmodulin. Structure 24:1441–1451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kameshima S, Okada M, Ikeda S, Watanabe Y, Yamawaki H (2016) Coordination of changes in expression and phosphorylation of eukaryotic elongation factor 2 (eEF2) and eEF2 kinase in hypertrophied cardiomyocytes. Biochem Biophys Rep 7:218–224

    PubMed  PubMed Central  Google Scholar 

  23. Diggle TA, Seehra CK, Hase S, Redpath NT (1999) Analysis of the domain structure of elongation factor-2 kinase by mutagenesis. FEBS Lett 457:189–192

    Article  CAS  PubMed  Google Scholar 

  24. Pigott CR, Mikolajek H, Moor E, Finn SJ, Phippe CW, Werner JM, Proud CG (2011) Insights into the regulation of eukaryotic elongation factor 2 kinase and the interplay between its domains. Biochem J 442:105–118

    Article  CAS  Google Scholar 

  25. Tavares CDJ, O’Brien JP, Abramczyk O, Devkota AK, Shores KS, Ozpolat B, Dalby K (2012) Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence. Biochemistry 51:2232–2245

    Article  CAS  PubMed  Google Scholar 

  26. Pyr Dit Ruys S, Wang X, Smith EM, Herinckx G, Hussain N, Rider MH, Vertommen D, Proud CG (2012) Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase. Biochem J 442:681–692

    Article  CAS  PubMed  Google Scholar 

  27. Jewell JL, Guan KL (2013) Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 38:233–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Redpath NT, Foulstone EJ, Proud CG (1996) Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J 15:2291–2297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Diggle TA, Subkhankulova T, Lilley KS, Shikotra N, Willis AE, Redpath NT (2001) Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/ calmodulin-independent activity. Biochem J 353:621–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Proud CG (2013) mTORC1 regulates the efficiency and cellular capacity for protein synthesis. Biochem Soc Trans 41:923–926

    Article  CAS  PubMed  Google Scholar 

  31. Wang X, Regufe da Mota S, Liu R, Moore CE, Xie J, Lanucara F, Agarwala U, Pyr Dit Ruys S, Vertommen D, Rider MH, Eyers CE, Proud CG (2014a) Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling. Mol Cell Biol 34:4088–4103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG (2001) Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase. EMBO J 20:4370–4379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hardie DG (2014) AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu Rev Nutr 34:31–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Browne GJ, Finn SG, Proud CG (2004) Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J Biol Chem 279:12220–12231

    Article  CAS  PubMed  Google Scholar 

  35. Johanns M, Ruys SPD, Houddane A, Vertommen D, Herinckx G, Hue L, Proud CG, Rider MH (2017) Direct and indirect activation of eukaryotic elongation factor 2 kinase by AMP-activated protein kinase. Cell Signal 36:212–221

    Article  CAS  PubMed  Google Scholar 

  36. Zona S, Bella L, Burton MJ, Nestal de Moraes G, Lam EW (2014) FOXM1: an emerging master regulator of DNA damage response and genotoxic agent resistance. Biochim Biophys Acta 1839:1316–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hamurcu Z, Ashour A, Kahraman N, Ozpolat B (2016) FOXM1 regulates expression of eukaryotic elongation factor 2 kinase and promotes proliferation, invasion and tumorgenesis of human triple negative breast cancer cells. Oncotarget 7:16619–16635

    Article  PubMed  PubMed Central  Google Scholar 

  38. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866

    Article  CAS  PubMed  Google Scholar 

  39. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838

    Article  CAS  PubMed  Google Scholar 

  40. Schwarzenbach H, Nishida N, Calin GA, Pantel K (2014) Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol 11:145–156

    Article  CAS  PubMed  Google Scholar 

  41. Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6:259–269

    Article  CAS  PubMed  Google Scholar 

  42. Pillai RS (2005) MicroRNA function: multiple mechanisms for a tiny RNA? RNA 11:1753–1761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen B, Li H, Zeng X, Yang P, Liu X, Zhao X, Liang S (2012) Roles of microRNA on cancer cell metabolism. J Transl Med 10:228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bayraktar R, Ivan C, Bayraktar E, Kanlikilicer P, Kabil NN, Kahraman N, Mokhlis HA, Karakas D, Rodriguez-Aguayo C, Arslan A, Sheng J, Wong S, Lopez-Berestein G, Calin GA, Ozpolat B (2018) Dual suppressive effect of miR-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasion. Clin Cancer Res 24:4225–4241

    Article  CAS  PubMed  Google Scholar 

  45. Shi Q, Xu X, Liu Q, Luo F, Shi J, He X (2016) MicroRNA-877 acts as a tumor suppressor by directly targeting eEF2K in renal cell carcinoma. Oncol Lett 11:1474–1480

    Article  CAS  PubMed  Google Scholar 

  46. Wu H, Zhu H, Liu DX, Niu TK, Ren X, Patel R, Hait WN, Yang JM (2009) Silencing of elongation factor-2 kinase potentiates the effect of 2-deoxy-D-glucose against human glioma cells through blunting of autophagy. Cancer Res 69:2453–2460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, Sood AK, Lopez-Berestein G, Dalby KN, Ozpolat B (2012) Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. PLoS One 7:e41171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ashour AA, Gurbuz N, Alpay SN, Abdel-Aziz AA, Mansour AM, Huo L, Ozpolat B (2014b) Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion. J Cell Mol Med 18:2235–2251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang L, Xu AM, Liu W (2015) Transglutaminase 2 in cancer. Am J Cancer Res 5:2756–2776

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Akar U, Ozpolat B, Mehta K, Fok J, Kondo Y, Lopez-Berestein G (2007) Tissue transglutaminase inhibits autophagy in pancreatic cancer cells. Mol Cancer Res 5:241–249

    Article  CAS  PubMed  Google Scholar 

  51. Zhang Y, Cheng Y, Zhang L, Ren X, Huber-Keener KJ, Lee S, Yun J, Wang HG, Yang JM (2011) Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-xL expression. Biochem Biophys Res Commun 414:129–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Filomeni G, De Zio D, Cecconi F (2015) Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ 22:377–388

    Article  CAS  PubMed  Google Scholar 

  54. Hamurcu Z, Delibaşı N, Geçene S, Şener EF, Dönmez-Altuntaş H, Özkul Y, Canatan H, Ozpolat B (2018) Targeting LC3 and Beclin-1 autophagy genes suppresses proliferation, survival, migration and invasion by inhibition of Cyclin-D1 and uPAR/Integrin β1/Src signaling in triple negative breast cancer cells. J Cancer Res Clin Oncol 144:415–430

    Article  CAS  PubMed  Google Scholar 

  55. Xie CM, Liu XY, Sham KW, Lai JM, Cheng CH (2014) Silencing of EEF2K (eukaryotic elongation factor-2 kinase) reveals AMPK-ULK1-dependent autophagy in colon cancer cells. Autophagy 10:1495–1508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15:155–162

    Article  CAS  PubMed  Google Scholar 

  58. Shimobayashi M, Hall MN (2016) Multiple amino acid sensing inputs to mTORC1. Cell Res 26:7–20

    Article  CAS  PubMed  Google Scholar 

  59. Heberle AM, Prentzell MT, van Eunen K, Bakker BM, Grellscheid SN, Thedieck K (2015) Molecular mechanisms of mTOR regulation by stress. Mol Cell Oncol 2:e970489

    Article  PubMed  CAS  Google Scholar 

  60. Egan D, Kim J, Shaw R, Guan KL (2011) The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7:643–644

    Article  PubMed  CAS  Google Scholar 

  61. Lindqvist LM, Tandoc K, Topisirovic I, Furic L (2018) Cross-talk between protein synthesis, energy metabolism and autophagy in cancer. Curr Opin Genet Dev 48:104–111

    Article  CAS  PubMed  Google Scholar 

  62. Rabanal-Ruiz Y, Otten EG, Korolchuk VI (2017) mTORC1 as the main gateway to autophagy. Essays Biochem 61:565–584

    Article  PubMed  PubMed Central  Google Scholar 

  63. Xu J, Ji J, Yan XH (2012) Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr 52:373–381

    Article  CAS  PubMed  Google Scholar 

  64. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu H, Yang JM, Jin S, Zhang H, Hait WN (2006) Elongation factor-2 kinase regulates autophagy in human glioblastoma cells. Cancer Res 66:3015–3023

    Article  CAS  PubMed  Google Scholar 

  66. Cheng Y, Ren X, Zhang Y, Shan Y, Huber-Keener KJ, Zhang L, Kimball SR, Harvey H, Jefferson LS, Yang JM (2013) Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells. Autophagy 9:208–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pinto JA, Rolfo C, Raez LE, Prado A, Araujo JM, Bravo L, Fajardo W, Morante ZD, Aguilar A, Neciosup SP, Mas LA, Bretel D, Balko JM, Gomez HL (2017) In silico evaluation of DNA damage inducible transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies. Sci Rep 7:1526

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Sun D, Zhu L, Zhao Y, Jiang Y, Chen L, Yu Y, Ouyang L (2018) Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer. Cell Prolif 51:e12402

    Article  PubMed  CAS  Google Scholar 

  69. Moore CE, Wang X, Xie J, Pickford J, Barron J, Regufe da Mota S, Versele M, Proud CG (2016) Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy. Cell Signal 28:284–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Karakas D, Kahraman N, Bayraktar R, Kabil N, Ulukaya E, Dere E, Lopez-Berestein G, Ozpolat B (2018) Identification of microenvironmental regulation and therapeutic targeting of ongenic EF-2 kinase in pancreatic cancer. (Conference paper). Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam. doi: https://doi.org/10.1136/esmoopen-2018-EACR25.803

  71. Xie J, Shen K, Lenchine RV, Gethings LA, Trim PJ, Snel MF, Zhou Y, Kenney JW, Kamei M, Kochetkova M, Wang X, Proud CG (2018) Eukaryotic elongation factor 2 kinase upregulates the expression of proteins implicated in cell migration and cancer cell metastasis. Int J Cancer 142:1865–1877

    Article  CAS  PubMed  Google Scholar 

  72. Zhou Y, Li Y, Xu S, Lu J, Zhu Z, Chen S, Tan Y, He P, Xu J, Proud CG, Xie J, Shen K (2019) Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3. Int J Cancer 146:1383–1395

    Article  PubMed  CAS  Google Scholar 

  73. Asik E, Kahraman N, Guray T, Volkan M, Lopez-Berestein G, Ozpolat B (2017) Eukaryotic elongation factor 2 kinase (eEF-2K) is a novel therapeutic target in BRCA1+ mutated breast cancer. (Conference paper). Cancer Res 77(13 Supplement):1125–1125

    Google Scholar 

  74. Cheng Y, Ren X, Zhang Y, Patel R, Sharma A, Wu H, Robertson GP, Yan L, Rubin E, Yang JM (2011) 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 71:2654–2663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hui L, Chen Y (2015) Tumor microenvironment: sanctuary of the devil. Cancer Lett 368:7–13

    Article  CAS  PubMed  Google Scholar 

  76. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, Hu G, Sun Y (2015) New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med 13:45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Witz IP (2008) Tumor-microenvironment interactions: dangerous liaisons. Adv Cancer Res 100:203–229

    Article  CAS  PubMed  Google Scholar 

  78. Li LY (2010) Tumor microenvironment: bidirectional interactions between cancer cells and normal cells. Protein Cell 1:702–705

    Article  PubMed  PubMed Central  Google Scholar 

  79. Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125:5591–5596

    Article  CAS  PubMed  Google Scholar 

  80. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322

    Article  CAS  PubMed  Google Scholar 

  82. Williams CB, Yeh ES, Soloff AC (2016) Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer 2:15025

    Article  PubMed  PubMed Central  Google Scholar 

  83. Naito Y, Yoshioka Y, Yamamoto Y, Ochiya T (2017) How cancer cells dictate their microenvironment: present roles of extracellular vesicles. Cell Mol Life Sci 74:697–713

    Article  CAS  PubMed  Google Scholar 

  84. Kanter JE (2017) Monocyte recruitment versus macrophage proliferation in atherosclerosis. Circ Res 121:1109–1110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L (1992) The origin and function of tumor-associated macrophages. Immunol Today 13:265–270

    Article  CAS  PubMed  Google Scholar 

  86. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14:399–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896

    Article  CAS  PubMed  Google Scholar 

  88. Tian W, Wang L, Yuan L, Duan W, Zhao W, Wang S, Zhang Q (2016) A prognostic risk model for patients with triple negative breast cancer based on stromal natural killer cells, tumor-associated macrophages and growth-arrest specific protein 6. Cancer Sci 107:882–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fang WB, Yao M, Brummer G, Acevedo D, Alhakamy N, Berkland C, Cheng N (2016) Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment. Oncotarget 7:49349–49367

    Article  PubMed  PubMed Central  Google Scholar 

  90. Wang H, Zhang Q, Kong H, Zeng Y, Hao M, Yu T, Peng J, Xu Z, Chen J, Shi H (2014b) Monocyte chemotactic protein-1 expression as a prognosic biomarker in patients with solid tumor: a meta analysis. Int J Clin Exp Pathol 7:3876–3886

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R, Sugano G, Kato Y, Li J, Pollard JW (2015) CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med 212:1043–1059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73:1128–1141

    Article  CAS  PubMed  Google Scholar 

  93. Chen JH, Riazy M, Smith EM, Proud CG, Steinbrecher UP, Duronio V (2009) Oxidized LDL-mediated macrophage survival involves elongation factor-2 kinase. Arterioscler Thromb Vasc Biol 29:92–98

    Article  CAS  PubMed  Google Scholar 

  94. Zhang P, Riazy M, Gold M, Tsai SH, McNagny K, Proud C, Duronio V (2014) Impairing eukaryotic elongation factor 2 kinase activity decreases atherosclerotic plaque formation. Can J Cardiol 30:1684–1688

    Article  PubMed  Google Scholar 

  95. Xu Z, Zhao L, Yang X, Ma S, Ge Y, Liu Y, Liu S, Shi J, Zheng D (2016) Mmu-miR-125b overexpression suppresses NO production in activated macrophages by targeting eEF2K and CCNA2. BMC Cancer 16:252

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Li S, Sun Y, Gao D (2013) Role of the nervous system in cancer metastasis. Oncol Lett 5:1101–1111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kayahara M, Nakagawara H, Kitagawa H, Ohta T (2007) The nature of neural invasion by pancreatic cancer. Pancreas 35:218–223

    Article  PubMed  Google Scholar 

  98. Seifert P, Benedic M, Effert P (2002) Nerve fibers in tumors of the human urinary bladder. Virchows Arch 440:291–297

    Article  CAS  PubMed  Google Scholar 

  99. Ventura S, Pennefather J, Mitchelson F (2002) Cholinergic innervation and function in the prostate gland. Pharmacol Ther 94:93–112

    Article  CAS  PubMed  Google Scholar 

  100. Mitchell BS, Schumacher U, Stauber VV, Kaiserling E (1994) Are breast tumours innervated? Immunohistological investigations using antibodies against the neuronal marker protein gene product 9.5 (PGP 9.5) in benign and malignant breast lesions. Eur J Cancer 30A:1100–1103

    Article  CAS  PubMed  Google Scholar 

  101. Seifert P, Spitznas M (2002) Axons in human choroidal melanoma suggest the participation of nerves in the control of these tumors. Am J Ophthalmol 133:711–713

    Article  PubMed  Google Scholar 

  102. Jobling P, Pundavela J, Oliveira SM, Roselli S, Walker MM, Hondermarck H (2015) Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res 75:1777–1781

    Article  CAS  PubMed  Google Scholar 

  103. Connolly E, Braunstein S, Formenti S, Schneider RJ (2006) Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol Cell Biol 26:3955–3965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kenney JW, Genheden M, Moon KM, Wang X, Foster LJ, Proud CG (2015) Eukaryotic elongation factor 2 kinase regulates the synthesis of microtubule-related proteins in neurons. J Neurochem 136:276–284

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10:767–777

    Article  CAS  PubMed  Google Scholar 

  106. Xie J, Mikolajek H, Pigott CR, Hooper KJ, Mellows T, Moore CE, Mohammed H, Werner JM, Thomas GJ, Proud CG (2015) Molecular mechanism for the control of eukaryotic elongation factor 2 kinase by pH: role in cancer cell survival. Mol Cell Biol 35:1805–1824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yamaguchi H, Matsushita M, Nairn AC, Kuriyan J (2001) Crystal structure of the atypical protein kinase domain of a TRP channel with phosphotransferase activity. Mol Cell 7:1047–1057

    Article  CAS  PubMed  Google Scholar 

  108. Ye Q, Crawley SW, Yang Y, Cote GP, Jia Z (2010) Crystal structure of the alpha-kinase domain of dictyostelium myosin heavy chain kinase A. Sci Signal 3:ra17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. De Gassart A, Demaria O, Panes R, Zaffalon L, Ryazanov AG, Gilliet M, Martinon F (2016) Pharmacological eEF2K activation promotes cell death and inhibits cancer progression. EMBO Rep 17:1471–1484

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Gschwendt M, Müller HJ, Kielbassa K, Zang R, Kittstein W, Rincke G, Marks F (1994a) Rottlerin, a novel protein kinase inhibitor. Biochem Biophys Res Commun 199:93–98

    Article  CAS  PubMed  Google Scholar 

  111. Gschwendt M, Kittstein W, Marks F (1994b) Elongation factor-2 kinase: effective inhibition by the novel protein kinase inhibitor rottlerin and relative insensitivity towards staurosporine. FEBS Lett 338:85–88

    Article  CAS  PubMed  Google Scholar 

  112. Davies SP, Reddy H, Caivano M, Cohen P (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cho SI, Koketsu M, Ishihara H, Matsushita M, Nairn AC, Fukazawa H, Uehara Y (2000) Novel compounds, ‘1,3-selenazine derivatives’ as specific inhibitors of eukaryotic elongation factor-2 kinase. Biochim Biophys Acta 1475:207–215

    Article  CAS  PubMed  Google Scholar 

  114. Hori H, Nagasawa H, Ishibashi M, Uto Y, Hirata A, Saijo K, Ohkura K, Kirk KL, Uehara Y (2002) TX-1123: an antitumor 2-hydroxyarylidene-4-cyclopentene-1,3-dione as a protein tyrosine kinase inhibitor having low mitochondrial toxicity. Bioorg Med Chem 10:3257–3265

    Article  CAS  PubMed  Google Scholar 

  115. Arora S, Yang JM, Kinzy TG, Utsumi R, Okamoto T, Kitayama T, Ortiz PA, Hait WN (2003) Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines. Cancer Res 63:6894–6899

    CAS  PubMed  Google Scholar 

  116. Chen Z, Gopalakrishnan SM, Bui MH, Soni NB, Warrior U, Johnson EF, Donnelly JB, Glaser KB (2011) 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 286:43951–43958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Devkota AK, Tavares CD, Warthaka M, Abramczyk O, Marshall KD, Kaoud TS, Gorgulu K, Ozpolat B, Dalby KN (2012) Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125: evidence of a common in vitro artifact. Biochemistry 51:2100–2112

    Article  CAS  PubMed  Google Scholar 

  118. Lockman JW, Reeder MD, Suzuki K, Ostanin K, Hoff R, Bhoite L, Austin H, Baichwal VJ, Willardsen JA (2010) Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues. Bioorg Med Chem Lett 20:2283–2286

    Article  CAS  PubMed  Google Scholar 

  119. Guo Y, Zhao Y, Wang G, Chen Y, Jiang Y, Ouyang L, Liu B (2018) Design, synthesis and structure-activity relationship of a focused library of β-phenylalanine derivatives as novel eEF2K inhibitors with apoptosis-inducing mechanisms in breast cancer. Eur J Med Chem 143:402–418

    Article  CAS  PubMed  Google Scholar 

  120. Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, Jones C, Radulescu S, Huels DJ, Myant KB, Dudek KM, Casey HA, Scopelliti A, Cordero JB, Vidal M, Pende M, Ryazanov AG, Sonenberg N, Meyuhas O, Hall MN, Bushell M, Willis AE, Sansom OJ (2015) mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 517:497–500

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Istinye University, Istanbul, Turkey

    Didem Karakas

  2. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Bulent Ozpolat

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  1. Didem Karakas
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  2. Bulent Ozpolat
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Karakas, D., Ozpolat, B. Eukaryotic elongation factor-2 kinase (eEF2K) signaling in tumor and microenvironment as a novel molecular target. J Mol Med 98, 775–787 (2020). https://doi.org/10.1007/s00109-020-01917-8

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  • DOI: https://doi.org/10.1007/s00109-020-01917-8

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