Tumor Biology

, Volume 36, Issue 11, pp 8617–8624 | Cite as

PARP3 interacts with FoxM1 to confer glioblastoma cell radioresistance

Research Article

Abstract

Poly(ADP-ribose) polymerase 3 (PARP3), a critical player in cellular response to DNA double-strand breaks (DSBs), plays an essential role in the maintenance of genome integrity. However, the role of PARP3 in tumorigenesis especially in glioblastoma remains largely unknown. In the present study, we found that the mRNA and protein levels of PARP3 were upregulated in primary glioblastoma tissues. Knockdown of PARP3 expression by lentivirus-based shRNA decreased cell glioblastoma proliferation and inhibited tumor growth in vivo by using a xenograft mouse model. Furthermore, we found that silencing the expression of PARP3 resulted in a synergistic radiosensitizing effect when combined with radiotherapy in glioblastoma cell lines. At the molecular level, we found that PARP3 interacted with FoxM1 to enhance its transcriptional activity and conferred glioblastoma cell radioresistance. Thus, our data suggest that PARP3 could be a therapeutic target to overcome radioresistance in glioblastoma.

Keywords

PARP3 Radioresistance Glioblastoma Apoptosis 

Notes

Conflicts of interest

None

References

  1. 1.
    Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507.CrossRefPubMedGoogle Scholar
  2. 2.
    Van Meir EG et al. Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin. 2010;60(3):166–93.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Kruh GD. Introduction to resistance to anticancer agents. Oncogene. 2003;22(47):7262–4.CrossRefPubMedGoogle Scholar
  4. 4.
    Perona R, Sanchez-Perez I. Control of oncogenesis and cancer therapy resistance. Br J Cancer. 2004;90(3):573–7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Erpolat OP et al. Outcome of newly diagnosed glioblastoma patients treated by radiotherapy plus concomitant and adjuvant temozolomide: a long-term analysis. Tumori. 2009;95(2):191–7.PubMedGoogle Scholar
  6. 6.
    Noda SE et al. Molecular advances of brain tumors in radiation oncology. Semin Radiat Oncol. 2009;19(3):171–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Augustin A et al. PARP-3 localizes preferentially to the daughter centriole and interferes with the G1/S cell cycle progression. J Cell Sci. 2003;116(Pt 8):1551–62.CrossRefPubMedGoogle Scholar
  8. 8.
    Rouleau M et al. PARP-3 associates with polycomb group bodies and with components of the DNA damage repair machinery. J Cell Biochem. 2007;100(2):385–401.CrossRefPubMedGoogle Scholar
  9. 9.
    Rulten SL et al. PARP-3 and APLF function together to accelerate nonhomologous end-joining. Mol Cell. 2011;41(1):33–45.CrossRefPubMedGoogle Scholar
  10. 10.
    Fenton AL et al. The PARP3- and ATM-dependent phosphorylation of APLF facilitates DNA double-strand break repair. Nucleic Acids Res. 2013;41(7):4080–92.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Beck C et al. PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways. Nucleic Acids Res. 2014;42(9):5616–32.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Langelier MF, Riccio AA, Pascal JM. PARP-2 and PARP-3 are selectively activated by 5′ phosphorylated DNA breaks through an allosteric regulatory mechanism shared with PARP-1. Nucleic Acids Res. 2014;42(12):7762–75.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang Z, et al. Glioblastoma multiforme formation and EMT: role of FoxM1 transcription factor. Curr Pharm Des. 2014;21(10):1268–71.Google Scholar
  14. 14.
    Zhang N et al. FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin Cancer Res. 2012;18(21):5961–71.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhang Y et al. FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells. Cancer Res. 2008;68(21):8733–42.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Dai B et al. Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells. Oncogene. 2007;26(42):6212–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu M et al. FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res. 2006;66(7):3593–602.CrossRefPubMedGoogle Scholar
  18. 18.
    Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012;47(4):497–510.CrossRefPubMedGoogle Scholar
  20. 20.
    Symington LS, Gautier J. Double-strand break end resection and repair pathway choice. Annu Rev Genet. 2011;45:247–71.CrossRefPubMedGoogle Scholar
  21. 21.
    Lieber MR, Wilson TE. SnapShot: nonhomologous DNA end joining (NHEJ). Cell. 2010;142(3):496. e1.CrossRefPubMedGoogle Scholar
  22. 22.
    Mohindra P et al. Non-cytotoxic radiosensitizers in brain radiotherapy: journey till the first decade of this millennium. Curr Cancer Drug Targets. 2012;12(3):260–78.CrossRefPubMedGoogle Scholar
  23. 23.
    Haar CP et al. Drug resistance in glioblastoma: a mini review. Neurochem Res. 2012;37(6):1192–200.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kesari S et al. DNA damage response and repair: insights into strategies for radiation sensitization of gliomas. Future Oncol. 2011;7(11):1335–46.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chinot OL et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–22.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of NeurosurgeryThe Second Affiliated Hospital of Xi’an Jiao Tong UniversityXi’anChina
  2. 2.Department of NeurosurgeryThe First Affiliated Hospital of Xi’an Jiao Tong UniversityXi’anChina

Personalised recommendations