Display options
Cite
Mehlich D, Łomiak M, Sobiborowicz A, et al. MLK4 regulates DNA damage response and promotes triple-negative breast cancer chemoresistance. Cell Death Dis. 2021;12(12):1111doi: 10.1038/s41419-021-04405-0.
Mehlich, D., Łomiak, M., Sobiborowicz, A., Mazan, A., Dymerska, D., Szewczyk, �. �. M., Mehlich, A., Borowiec, A., Prełowska, M. K., Gorczyński, A., Jabłoński, P., Iżycka-Świeszewska, E., Nowis, D., & Marusiak, A. A. (2021). MLK4 regulates DNA damage response and promotes triple-negative breast cancer chemoresistance. Cell death & disease, 12(12), 1111. https://doi.org/10.1038/s41419-021-04405-0
Mehlich, Dawid, et al. "MLK4 regulates DNA damage response and promotes triple-negative breast cancer chemoresistance." Cell death & disease vol. 12,12 (2021): 1111. doi: https://doi.org/10.1038/s41419-021-04405-0
Mehlich D, Łomiak M, Sobiborowicz A, Mazan A, Dymerska D, Szewczyk ŁM, Mehlich A, Borowiec A, Prełowska MK, Gorczyński A, Jabłoński P, Iżycka-Świeszewska E, Nowis D, Marusiak AA. MLK4 regulates DNA damage response and promotes triple-negative breast cancer chemoresistance. Cell Death Dis. 2021 Nov 27;12(12):1111. doi: 10.1038/s41419-021-04405-0. PMID: 34839359; PMCID: PMC8627512.
Copy Download .nbib Format: NLM
Share it on

Cell Death Dis. 2021 Nov 27;12(12):1111. doi: 10.1038/s41419-021-04405-0.

MLK4 regulates DNA damage response and promotes triple-negative breast cancer chemoresistance.

Cell death & disease

Dawid Mehlich, Michał Łomiak, Aleksandra Sobiborowicz, Alicja Mazan, Dagmara Dymerska, Łukasz M Szewczyk, Anna Mehlich, Agnieszka Borowiec, Monika K Prełowska, Adam Gorczyński, Paweł Jabłoński, Ewa Iżycka-Świeszewska, Dominika Nowis, Anna A Marusiak

Affiliations

  1. Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Warsaw, Poland.
  2. Doctoral School of Medical University of Warsaw, Warsaw, Poland.
  3. Laboratory of Experimental Medicine, Medical University of Warsaw, Warsaw, Poland.
  4. Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  5. Department of Experimental and Clinical Physiology, Medical University of Warsaw, Warsaw, Poland.
  6. ReMedy International Research Agenda Unit, IMol Polish Academy of Sciences, Warsaw, Poland.
  7. Laboratory of Molecular Neurobiology, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  8. Department of Internal Diseases Endocrinology and Diabetes, Medical University of Warsaw, Warsaw, Poland.
  9. Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
  10. Department of Pathology and Neuropathology, Faculty of Health Sciences, Medical University of Gdansk, Gdansk, Poland.
  11. Department of Pathomorphology, Copernicus P.L., Gdansk, Poland.
  12. Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
  13. Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Warsaw, Poland. [email protected].
  14. ReMedy International Research Agenda Unit, IMol Polish Academy of Sciences, Warsaw, Poland. [email protected].

PMID: 34839359 PMCID: PMC8627512 DOI: 10.1038/s41419-021-04405-0

Abstract

Chemoresistance constitutes a major challenge in the treatment of triple-negative breast cancer (TNBC). Mixed-Lineage Kinase 4 (MLK4) is frequently amplified or overexpressed in TNBC where it facilitates the aggressive growth and migratory potential of breast cancer cells. However, the functional role of MLK4 in resistance to chemotherapy has not been investigated so far. Here, we demonstrate that MLK4 promotes TNBC chemoresistance by regulating the pro-survival response to DNA-damaging therapies. We observed that MLK4 knock-down or inhibition sensitized TNBC cell lines to chemotherapeutic agents in vitro. Similarly, MLK4-deficient cells displayed enhanced sensitivity towards doxorubicin treatment in vivo. MLK4 silencing induced persistent DNA damage accumulation and apoptosis in TNBC cells upon treatment with chemotherapeutics. Using phosphoproteomic profiling and reporter assays, we demonstrated that loss of MLK4 reduced phosphorylation of key DNA damage response factors, including ATM and CHK2, and compromised DNA repair via non-homologous end-joining pathway. Moreover, our mRNA-seq analysis revealed that MLK4 is required for DNA damage-induced expression of several NF-кB-associated cytokines, which facilitate TNBC cells survival. Lastly, we found that high MLK4 expression is associated with worse overall survival of TNBC patients receiving anthracycline-based neoadjuvant chemotherapy. Collectively, these results identify a novel function of MLK4 in the regulation of DNA damage response signaling and indicate that inhibition of this kinase could be an effective strategy to overcome TNBC chemoresistance.

© 2021. The Author(s).

References

  1. Cell. 2010 Oct 29;143(3):355-66 - PubMed
  2. Science. 2007 May 25;316(5828):1160-6 - PubMed
  3. Pharmacol Ther. 2015 May;149:124-38 - PubMed
  4. Nat Rev Clin Oncol. 2016 Nov;13(11):674-690 - PubMed
  5. EMBO J. 2009 Nov 4;28(21):3413-27 - PubMed
  6. Oncogene. 2013 Apr 4;32(14):1854-62 - PubMed
  7. Elife. 2015 Jun 01;4: - PubMed
  8. Biology (Basel). 2014 May 30;3(2):345-67 - PubMed
  9. J Clin Oncol. 2011 Apr 20;29(12):1578-86 - PubMed
  10. Cell Signal. 2017 Nov;39:66-73 - PubMed
  11. Trends Cancer. 2020 Jun;6(6):489-505 - PubMed
  12. Science. 2006 Feb 24;311(5764):1141-6 - PubMed
  13. PLoS Genet. 2008 Jun 27;4(6):e1000110 - PubMed
  14. Chem Biol. 2010 May 28;17(5):421-33 - PubMed
  15. Cancer Cell. 2016 Feb 8;29(2):201-13 - PubMed
  16. Cancer Res. 2016 Feb 1;76(3):724-35 - PubMed
  17. Oncogenesis. 2012 Mar 26;1:e6 - PubMed
  18. Mol Cancer Ther. 2009 Oct;8(10):2894-902 - PubMed
  19. Cancer Res. 2013 Mar 15;73(6):1912-21 - PubMed
  20. Sci Signal. 2014 May 13;7(325):rs3 - PubMed
  21. Cancer Res. 2004 Dec 15;64(24):9152-9 - PubMed
  22. J Biol Chem. 2011 Mar 18;286(11):9107-19 - PubMed
  23. Nat Commun. 2014 May 22;5:3901 - PubMed
  24. Leukemia. 2019 Oct;33(10):2365-2378 - PubMed
  25. Clin Cancer Res. 2016 Aug 1;22(15):3764-73 - PubMed
  26. Cell Res. 2011 Jan;21(1):116-30 - PubMed
  27. Genes Dev. 1999 Oct 15;13(20):2633-8 - PubMed
  28. Ann Oncol. 2019 Sep 1;30(9):1437-1447 - PubMed
  29. Mol Cell. 2019 Aug 22;75(4):669-682.e5 - PubMed
  30. J Biol Chem. 2004 Dec 17;279(51):53272-81 - PubMed
  31. Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210 - PubMed
  32. Cell Death Dis. 2017 Jul 13;8(7):e2932 - PubMed
  33. In Vivo. 2008 May-Jun;22(3):305-9 - PubMed
  34. Cancer Discov. 2012 May;2(5):401-4 - PubMed
  35. Cell. 2003 Nov 26;115(5):565-76 - PubMed
  36. Clin Transl Med. 2018 Sep 3;7(1):27 - PubMed
  37. N Engl J Med. 2010 Nov 11;363(20):1938-48 - PubMed
  38. PLoS Genet. 2019 Oct 4;15(10):e1008355 - PubMed
  39. Cancer Lett. 2021 Jun 1;507:13-25 - PubMed
  40. Curr Med Chem. 2015;22(2):264-89 - PubMed
  41. Pharmacol Ther. 2019 Nov;203:107391 - PubMed
  42. Cancer Res. 2003 Sep 15;63(18):5978-91 - PubMed
  43. Mol Cell. 2010 Oct 22;40(2):179-204 - PubMed
  44. Crit Rev Oncol Hematol. 2019 Jun;138:214-222 - PubMed
  45. Oncogene. 2019 Apr;38(15):2860-2875 - PubMed
  46. J Clin Med. 2020 Mar 30;9(4): - PubMed
  47. Lancet. 2014 Jul 12;384(9938):164-72 - PubMed
  48. Cell. 2012 Jul 6;150(1):165-78 - PubMed
  49. Cancer Res. 2018 Feb 1;78(3):742-757 - PubMed
  50. Nat Commun. 2020 May 29;11(1):2662 - PubMed
  51. Mol Biol Cell. 2008 Aug;19(8):3283-9 - PubMed
  52. Exp Mol Med. 2010 Mar 31;42(3):195-204 - PubMed
  53. Cancer Discov. 2017 Jan;7(1):20-37 - PubMed
  54. Pharmacol Ther. 2020 Mar;207:107457 - PubMed
  55. J Clin Oncol. 2008 Mar 10;26(8):1275-81 - PubMed

Publication Types

Grant support