Article | Published:

Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia

Oncogenevolume 37pages41814196 (2018) | Download Citation


Poor oxygenation is a common hallmark of solid cancers that strongly associates with aggressive tumor progression and treatment resistance. While a hypoxia-inducible factor 1α (HIF-1α)-associated transcriptional overexpression of the hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) MET has been previously documented, any regulation of the HIF-1α system through MET downstream signaling in hypoxic tumors has not been yet described. By using MET-driven in vitro as well as ex vivo tumor organotypic fresh tissue models we report that MET targeting results in depletion of HIF-1α and its various downstream targets. Mechanistically, we provide evidence that MET regulates HIF-1α levels through a protein translation mechanism that relies on phosphorylation modulation of the eukaryotic initiation factor 4G1 (eIF4G1) on serine 1232 (Ser-1232). Targeted phosphoproteomics data demonstrate a significant drop in eIF4G1 Ser-1232 phosphorylation following MET targeting, which is linked to an increased affinity between eIF4G1 and eIF4E. Since phosphorylation of eIF4G1 on Ser-1232 is largely mediated through mitogen-activated protein kinase (MAPK), we show that expression of a constitutively active K-RAS variant is sufficient to abrogate the inhibitory effect of MET targeting on the HIF-1α pathway with subsequent resistance of tumor cells to MET targeting under hypoxic conditions. Analysis of The Cancer Genome Atlas data demonstrates frequent co-expression of MET, HIF-1α and eIF4G1 in various solid tumors and its impact on disease-free survival of non-small cell lung cancer patients. Clinical relevance of the MET-eIF4G1-HIF-1α pathway is further supported by a co-occurrence of their expression in common tumor regions of individual lung cancer patients.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Brahimi-Horn MC, Chiche J, Pouyssegur J. Hypoxia and cancer. J Mol Med. 2007;85:1301–7.

  2. 2.

    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science . 2005;307:58–62.

  3. 3.

    Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47.

  4. 4.

    Michieli P. Hypoxia, angiogenesis and cancer therapy: to breathe or not to breathe? Cell Cycle. 2009;8:3291–6.

  5. 5.

    Semenza GL. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell . 2001;107:1–3.

  6. 6.

    Clara CA, Marie SK, de Almeida JR, Wakamatsu A, Oba-Shinjo SM, Uno M, et al. Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1alpha in human glioblastoma. Neuropathology. 2014;34:343–52.

  7. 7.

    Boccaccio C, Comoglio PM. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer. 2006;6:637–45.

  8. 8.

    Ide T, Kitajima Y, Miyoshi A, Ohtsuka T, Mitsuno M, Ohtaka K, et al. Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway. Int J Cancer J Int du Cancer. 2006;119:2750–9.

  9. 9.

    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.

  10. 10.

    Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347–61.

  11. 11.

    Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1–26.

  12. 12.

    Liu X, Yao W, Newton RC, Scherle PA. Targeting the c-MET signaling pathway for cancer therapy. Expert Opin Investig Drugs. 2008;17:997–1011.

  13. 13.

    Zeng ZS, Weiser MR, Kuntz E, Chen CT, Khan SA, Forslund A, et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 2008;265:258–69.

  14. 14.

    Okuda K, Sasaki H, Yukiue H, Yano M, Fujii Y. Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci. 2008;99:2280–5.

  15. 15.

    Seiwert TY, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El Dinali M, et al. The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res. 2009;69:3021–31.

  16. 16.

    Cosse JP, Michiels C. Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anti-Cancer Agents Med Chem. 2008;8:790–7.

  17. 17.

    Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci Usa. 2006;103:2316–21.

  18. 18.

    Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science . 2007;316:1039–43.

  19. 19.

    Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov. 2008;7:504–16.

  20. 20.

    Vordermark D, Horsman MR. Hypoxia as a biomarker and for personalized radiation oncology: recent results. Cancer Res. 2016;198:123–42.

  21. 21.

    Boeckx C, Van den Bossche J, De Pauw I, Peeters M, Lardon F, Baay M, et al. The hypoxic tumor microenvironment and drug resistance against EGFR inhibitors: preclinical study in cetuximab-sensitive head and neck squamous cell carcinoma cell lines. BMC Res Notes. 2015;8:203.

  22. 22.

    Neill T, Painter H, Buraschi S, Owens RT, Lisanti MP, Schaefer L, et al. Decorin antagonizes the angiogenic network: concurrent inhibition of Met, hypoxia inducible factor 1alpha, vascular endothelial growth factor A, and induction of thrombospondin-1 and TIMP3. J Biol Chem. 2012;287:5492–506.

  23. 23.

    Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem. 2001;276:9519–25.

  24. 24.

    Minchenko OH, Tsuchihara K, Minchenko DO, Bikfalvi A, Esumi H. Mechanisms of regulation of PFKFB expression in pancreatic and gastric cancer cells. World J Gastroenterol. 2014;20:13705–17.

  25. 25.

    Minchenko O, Opentanova I, Minchenko D, Ogura T, Esumi H. Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1alpha activation. FEBS Lett. 2004;576:14–20.

  26. 26.

    Obach M, Navarro-Sabate A, Caro J, Kong X, Duran J, Gomez M, et al. 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia. J Biol Chem. 2004;279:53562–70.

  27. 27.

    Badura M, Braunstein S, Zavadil J, Schneider RJ. DNA damage and eIF4G1 in breast cancer cells reprogram translation for survival and DNA repair mRNAs. Proc Natl Acad Sci Usa. 2012;109:18767–72.

  28. 28.

    Pelletier J, Graff J, Ruggero D, Sonenberg N. Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res. 2015;75:250–63.

  29. 29.

    Dobrikov MI, Dobrikova EY, Gromeier M. Dynamic regulation of the translation initiation helicase complex by mitogenic signal transduction to eukaryotic translation initiation factor 4G. Mol Cell Biol. 2013;33:937–46.

  30. 30.

    Tarun SZ Jr., Sachs AB. Binding of eukaryotic translation initiation factor 4E (eIF4E) to eIF4G represses translation of uncapped mRNA. Mol Cell Biol. 1997;17:6876–86.

  31. 31.

    Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GFMet. metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915–25.

  32. 32.

    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604–13.

  33. 33.

    Gluck AA, Aebersold DM, Zimmer Y, Medova M. Interplay between receptor tyrosine kinases and hypoxia signaling in cancer. Int J Biochem Cell Biol. 2015;62:101–14.

  34. 34.

    Thangasamy A, Rogge J, Ammanamanchi S. Recepteur d’origine nantais tyrosine kinase is a direct target of hypoxia-inducible factor-1alpha-mediated invasion of breast carcinoma cells. J Biol Chem. 2009;284:14001–10.

  35. 35.

    Ikeda E, Achen MG, Breier G, Risau W. Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem. 1995;270:19761–6.

  36. 36.

    Paatero I, Seagroves TN, Vaparanta K, Han W, Jones FE, Johnson RS, et al. Hypoxia-inducible factor-1alpha induces ErbB4 signaling in the differentiating mammary gland. J Biol Chem. 2014;289:22459–69.

  37. 37.

    Cheng JC, Klausen C, Leung PC. Hypoxia-inducible factor 1 alpha mediates epidermal growth factor-induced down-regulation of E-cadherin expression and cell invasion in human ovarian cancer cells. Cancer Lett. 2013;329:197–206.

  38. 38.

    Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001;21:3995–4004.

  39. 39.

    Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res. 2006;66:3197–204.

  40. 40.

    Paatero I, Jokilammi A, Heikkinen PT, Iljin K, Kallioniemi OP, Jones FE, et al. Interaction with ErbB4 promotes hypoxia-inducible factor-1alpha signaling. J Biol Chem. 2012;287:9659–71.

  41. 41.

    Skuli N, Monferran S, Delmas C, Lajoie-Mazenc I, Favre G, Toulas C, et al. Activation of RhoB by hypoxia controls hypoxia-inducible factor-1alpha stabilization through glycogen synthase kinase-3 in U87 glioblastoma cells. Cancer Res. 2006;66:482–9.

  42. 42.

    Takacova M, Bullova P, Simko V, Skvarkova L, Poturnajova M, Feketeova L, et al. Expression pattern of carbonic anhydrase IX in Medullary thyroid carcinoma supports a role for RET-mediated activation of the HIF pathway. Am J Pathol. 2014;184:953–65.

  43. 43.

    Gariboldi MB, Ravizza R, Monti E. The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells. Biochem Pharmacol. 2010;80:455–62.

  44. 44.

    Villa N, Do A, Hershey JW, Fraser CS. Human eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c, -d, and -e to promote mRNA recruitment to the ribosome. J Biol Chem. 2013;288:32932–40.

  45. 45.

    Medova M, Pochon B, Streit B, Blank-Liss W, Francica P, Stroka D, et al. The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants. Mol Cancer Ther. 2013;12:2415–24.

  46. 46.

    Francica P, Nisa L, Aebersold DM, Langer R, Bladt F, Blaukat A, et al. Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer. Clin Cancer Res. 2016;22:5322–36.

  47. 47.

    Leiser D, Medova M, Mikami K, Nisa L, Stroka D, Blaukat A, et al. KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET-expressing tumor cells. Mol Oncol. 2015;9:1434–46.

  48. 48.

    Fuhrer T, Heer D, Begemann B, Zamboni N. High-throughput, accurate mass metabolome profiling of cellular extracts by flow injection-time-of-flight mass spectrometry. Anal Chem. 2011;83:7074–80.

  49. 49.

    Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Ser B. 1995;57:289–300.

  50. 50.

    Berezowska S, Galvan JA, Langer R, Bubendorf L, Savic S, Gugger M, et al. Glycine decarboxylase and HIF-1alpha expression are negative prognostic factors in primary resected early-stage non-small cell lung cancer. Virchows Arch. 2017;470:323–30.

Download references


We cordially thank Dr. Nicola Zamboni (ETH Zürich, Switzerland) for his help with metabolomics measurements and data analysis.


This work has been supported by Stiftung für klinisch-experimentelle Tumorforschung (grant to YZ) and by Stiftung zur Krebsbekämpfung (grant Nr.374/2016 to MM). YZ received a drug donation from Merck / EMD Serono. Merck / EMD Serono has reviewed the publication, and the views and opinions described in the publication do not necessarily reflect those of Merck.

Author information


  1. Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, 3010, Switzerland

    • Astrid A. Glück
    • , Eleonora Orlando
    • , Dominic Leiser
    • , Michaela Poliaková
    • , Lluís Nisa
    • , Aurélie Quintin
    • , Daniel M. Aebersold
    • , Michaela Medová
    •  & Yitzhak Zimmer
  2. Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, 3008, Switzerland

    • Astrid A. Glück
    • , Eleonora Orlando
    • , Michaela Poliaková
    • , Lluís Nisa
    • , Aurélie Quintin
    • , Daniel M. Aebersold
    • , Michaela Medová
    •  & Yitzhak Zimmer
  3. Department for BioMedical Research, Visceral and Transplantation Surgery, Inselspital, Bern University Hospital, and University of Bern, Bern, 3008, Switzerland

    • Jacopo Gavini
    •  & Deborah M. Stroka
  4. Institute of Pathology, University of Bern, Bern, 3008, Switzerland

    • Sabina Berezowska
  5. Institute of Pathology, Basel University Hospital, Basel, 4031, Switzerland

    • Lukas Bubendorf
  6. Global Research & Development, Merck KGaA, Darmstadt, 64293, Germany

    • Andree Blaukat


  1. Search for Astrid A. Glück in:

  2. Search for Eleonora Orlando in:

  3. Search for Dominic Leiser in:

  4. Search for Michaela Poliaková in:

  5. Search for Lluís Nisa in:

  6. Search for Aurélie Quintin in:

  7. Search for Jacopo Gavini in:

  8. Search for Deborah M. Stroka in:

  9. Search for Sabina Berezowska in:

  10. Search for Lukas Bubendorf in:

  11. Search for Andree Blaukat in:

  12. Search for Daniel M. Aebersold in:

  13. Search for Michaela Medová in:

  14. Search for Yitzhak Zimmer in:

Conflict of interest

AB is listed as a co-inventor on all patents related to Merck’s c-Met inhibitor referred to in this manuscript. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Yitzhak Zimmer.

Electronic supplementary material

About this article

Publication history