ATM inhibition prevents interleukin-6 from contributing to the proliferation of glioblastoma cells after ionizing radiation

  • Yi Chieh Lim
  • Hazel Quek
  • Carolin Offenhäuser
  • Shazrul Fazry
  • Andrew Boyd
  • Martin Lavin
  • Tara Roberts
  • Bryan Day
Laboratory Investigation

Abstract

Glioblastoma (GBM) is a highly fatal disease with a 5 year survival rate of less than 22%. One of the most effective treatment regimens to date is the use of radiotherapy which induces lethal DNA double-strand breaks to prevent tumour growth. However, recurrence occurs in the majority of patients and is in-part a result of robust radioresistance mechanisms. In this study, we demonstrate that the multifunctional cytokine, interleukin-6 (IL-6), confers a growth advantage in GBM cells but does not have the same effect on normal neural progenitor cells. Further analysis showed IL-6 can promote radioresistance in GBM cells when exposed to ionising radiation. Ablation of the Ataxia-telangiectasia mutated serine/threonine kinase that is recruited and activated by DNA double-strand breaks reverses the effect of radioresistance and re-sensitised GBM to DNA damage thus leading to increase cell death. Our finding suggests targeting the signaling cascade of DNA damage response is a potential therapeutic approach to circumvent IL-6 from promoting radioresistance in GBM.

Keywords

Interleukin-6 Glioblastoma DNA damage response Ataxia-telangiectasia mutated Inhibitor 

Notes

Acknowledgements

This work was generously supported by the Cancer Institute New South Wales Future Research Leader fellowship.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

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References

  1. 1.
    Kuilman T, Michaloglou C, Vredeveld LCW, Douma S, Doorn RV, Desmet CJ et al (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133(6):1019–1031CrossRefPubMedGoogle Scholar
  2. 2.
    Rodier F, Coppé J-P, Patil CK, Hoeijmakers WAM, Muñoz DP, Raza SR et al (2009) Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11(8):973–979CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lavin MF, Kozlov S (2007) ATM activation and DNA damage response. Cell Cycle 6(8):931–942CrossRefPubMedGoogle Scholar
  4. 4.
    Jones SA, Scheller J, Rose-John S (2011) Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Investig 121(9):3375–3383CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA et al (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23(12):2369–2380CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Sebastian T, Malik R, Thomas S, Sage J, Johnson PF (2005) C/EBP cooperates with RB:E2F to implement RasV12-induced cellular senescence. EMBO J 24:3301–3312CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bromberg J, Wang TC (2009) Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15(2):79–80CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Slinger E, Maussang D, Schreiber A, Siderius M, Rahbar A, Fraile-Ramos A et al (2010) HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6—STAT3 axis. Sci Signal 3(133):ra58CrossRefPubMedGoogle Scholar
  10. 10.
    Sun S, Steinberg BM (2002) PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells. J Gen Virol 83:1651–1658CrossRefPubMedGoogle Scholar
  11. 11.
    Muromoto R, Ikeda O, Okabe K, Togi S, Kamitani S, Fujimuro M et al (2008) Epstein–Barr virus-derived EBNA2 regulates STAT3 activation. Biochem Biophys Res Commun 378(3):439–43CrossRefPubMedGoogle Scholar
  12. 12.
    Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41(16):2502–2512CrossRefPubMedGoogle Scholar
  13. 13.
    Brown K, Tompkins EM, Boocock DJ, Martin EA, Farmer PB, Turteltaub KW et al (2007) Tamoxifen forms DNA adducts in human colon after administration of a single [14C]-labeled therapeutic dose. Can Res 67(14):6995–7002CrossRefGoogle Scholar
  14. 14.
    Iliopoulos D, Hirsch HA, Struhl K (2009) An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139:693–706CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Micco RD, Fumagalli M, Fagnagna FdAd (2007) Breaking news: high-speed race ends in arrest—how oncogenes induced senescence. Trends Cell Biol 17(11):529–536CrossRefPubMedGoogle Scholar
  16. 16.
    Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ et al (2002) Epidermal growth factor receptor and INK4a/Arf convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1(3):269–277CrossRefPubMedGoogle Scholar
  17. 17.
    Lim YC, Roberts TL, Day BW, Harding A, Kozlov S, Kijas AW et al (2012) A role for homologous recombination and abnormal cell cycle progression in radioresistance glioma initiating cells. Mol Cancer Ther 11(9):1863–1872CrossRefPubMedGoogle Scholar
  18. 18.
    McLendon R (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRefGoogle Scholar
  19. 19.
    Micco RD, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C et al (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:638–642CrossRefPubMedGoogle Scholar
  20. 20.
    Rolhion C, Penault-Llorca F, Kémény JL, Lemaire JJ, Jullien C, Labit-Bouvier C et al (2001) Interleukin-6 overexpression as a marker of malignancy in human gliomas. J Neurosurg 94(1):97–101CrossRefPubMedGoogle Scholar
  21. 21.
    Tchirkov AA, Khalil T, Chautard E, Mokhtari K, Véronèse L, Irthum B et al (2007) Interleukin-6 gene amplification and shortened survival in glioblastoma patients. Br J Cancer 96:474–476CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Eruslanov E, Kusmartsev S (2010) Review of cellular ROS generation and antioxidant defense mechanisms and methods for their analysis using H2DCFDA. Methods Mol Biol 594:57–72CrossRefPubMedGoogle Scholar
  23. 23.
    Hampel H, Haslinger A, Scheloske M, Padberg F, Fischer P, JosefUnger et al (2005) Pattern of interleukin-6 receptor complex immunoreactivity between cortical regions of rapid autopsy normal and Alzheimer’s disease brain. Eur Arch Psychiatry Clin Neurosci 225:269–278CrossRefGoogle Scholar
  24. 24.
    Roberts TL, Ho U, Luff J, Lee CS, Apte SH, MacDonald KPA et al. (2013) Smg1 haploinsufficiency predisposes to tumor formation and inflammation. Proc Natl Acad Sci 110(4):E285–E294CrossRefGoogle Scholar
  25. 25.
    Schreck I, Grico N, Hansjosten I, Marquardt C, Bormann S, Seidel A et al (2016) The nucleotide excision repair protein XPC is essential for bulky DNA adducts to promote interleukin-6 expression via the activation of p38-SAPK. Oncogene 35(7):908–918CrossRefPubMedGoogle Scholar
  26. 26.
    Sallmann S, Juttler E, Prinz S, Petersen N, Knopf U, Weiser T et al (2000) Induction of Interleukin-6 by depolarization of neurons. J Neurosci 20(23):8637–8642PubMedGoogle Scholar
  27. 27.
    McFarland BC, Hong SW, Rajbhandari R, Twitty GB Jr, Gray GK, Yu H et al (2013) NF-kappaB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma. PLoS ONE 8(11):e78728CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yamagiwa Y, Meng F, Patel T (2006) Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes. Life Sci 78(21):2494–2502CrossRefPubMedGoogle Scholar
  29. 29.
    Lim YC, Roberts TL, Day BW, Stringer BW, Kozlov S, Fazry S et al (2014) Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells. Mol Oncol 8(8):1603–1615CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gilbert LA, Hemann MT (2010) DNA damage-mediated induction of a chemoresistant niche. Cell 143:355–366CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ermolaeva MA, Schumacher B (2014) Systemic DNA damage responses: organismal adaptations to genome instability. Trends Genet 30(3):95–102CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Quek H, Lim YC, Lavin MF, Roberts TL (2018) PIKKing a way to regulate inflammation. Immunol Cell Biol 96(1):8–20CrossRefPubMedGoogle Scholar
  33. 33.
    Kennedy A, Adams PD. (2010) The senescence secretome and its impact on tumor suppression and cancer. Curr Cancer Res 3:139–154Google Scholar
  34. 34.
    Islam O, Gong X, Rose-John S, Heese K (2009) Interleukin-6 and neural stem cells: more than gliogenesis. Mol Biol Cell 20(1):188–199CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Drost J, Agami R (2009) Transformation locked in a loop. Cell 139:654–655CrossRefPubMedGoogle Scholar
  36. 36.
    Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A et al (2007) Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updates 10:13–29CrossRefGoogle Scholar
  37. 37.
    Sampetrean O, Saga I, Nakanishi M, Sugihara E, Osuka S, Akahata M et al (2011) Invasion precedes tumor mass formation in a malignant brain tumor model of genetically modified neural stem cells. Neoplasia 13(9):784–791CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J, Bernier G (2009) BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29(28):8884–8896CrossRefPubMedGoogle Scholar
  39. 39.
    Camacho CV, Todorova PK, Hardebeck MC, Tomimatsu N, Alcazar CRGD, Ilcheva M et al (2015) DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification. Oncogene 34:1064–1072CrossRefPubMedGoogle Scholar
  40. 40.
    Jiang XP, Yang DC, Elliott RL, Head JF (2011) Down-regulation of expression of interleukin-6 and its receptor results in growth inhibition of MCF-7 breast cancer cells. Anticancer Res 31(9):2899–2906PubMedGoogle Scholar
  41. 41.
    Lin L, Benson D, DeAngelis S, Bakan CE, Li PK, Li C et al (2012) A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human multiple myeloma cells. Int J Cancer 130(6):1459–1469CrossRefPubMedGoogle Scholar
  42. 42.
    Siewert E, ller-Esterl WM, Starr R, Heinrich PC, Schaper F (1999) Different protein turnover of interleukin-6-type cytokine signalling components. Eur J Biochem 265:251–257CrossRefPubMedGoogle Scholar
  43. 43.
    Miyamoto S (2011) Nuclear initiated NF-kB signaling: NEMO and ATM take center stage. Cell Res 21(1):116–130CrossRefPubMedGoogle Scholar
  44. 44.
    Wu Z-H, Shi Y, Tibbetts RS, Miyamoto S (2006) Molecular linkage between the kinase ATM and NF-κB signaling in response to genotoxic stimuli. Science 311:1141–1146CrossRefPubMedGoogle Scholar
  45. 45.
    Biton S, Ashkenazi A (2011) NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-a feedforward signaling. Cell 145:92–103CrossRefPubMedGoogle Scholar
  46. 46.
    Squarize CH, Castilho RM, Sriuranpong V, Pinto DS, Gutkind JS (2006) Molecular cross-talk between the NFKB and STAT3 signaling pathways in head and neck squamous cell carcinoma. Neoplasia 8(9):733–746CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Tas SW, Jong ECD, Hajji N, May MJ, Ghosh S, Vervoordeldonk MJ et al (2005) Selective inhibition of NF-kB in dendritic cells by the NEMO-binding domain peptide blocks maturation and prevents T cell proliferation and polarization. Eur J Immunol 35(4):1164–1174CrossRefPubMedGoogle Scholar
  48. 48.
    Jin X, Yin J, Kim S-H, Sohn Y-W, Beck S, Lim YC et al (2011) EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. Cancer Res 71:7125–7134CrossRefPubMedGoogle Scholar
  49. 49.
    Heimberger AB, Suki D, Yang D, Shi W, Aldape K (2005) The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med 3:38–44CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yi Chieh Lim
    • 1
  • Hazel Quek
    • 1
  • Carolin Offenhäuser
    • 1
  • Shazrul Fazry
    • 2
  • Andrew Boyd
    • 1
  • Martin Lavin
    • 3
  • Tara Roberts
    • 4
    • 5
  • Bryan Day
    • 1
  1. 1.Translational Brain Cancer Research Laboratory, Cell and Molecular Biology DepartmentQIMR Berghofer MRIBrisbaneAustralia
  2. 2.School of Bioscience and Biotechnology, Faculty of Science and TechnologyUniversiti Kebangsaan MalaysiaSelangorMalaysia
  3. 3.Faculty of MedicineThe University of Queensland Centre for Clinical ResearchHerston, BrisbaneAustralia
  4. 4.Ingham Institute for Applied Medical Research and School of MedicineWestern Sydney UniversityLiverpool, SydneyAustralia
  5. 5.South West Sydney Clinical SchoolUNSW SydneyKensington, SydneyAustralia

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