DOI QR코드

DOI QR Code

Downregulation of FoxM1 sensitizes nasopharyngeal carcinoma cells to cisplatin via inhibition of MRN-ATM-mediated DNA repair

Li, Dandan;Ye, Lin;Lei, Yue;Wan, Jie;Chen, Hongyan

  • Received : 2018.10.27
  • Accepted : 2019.01.10
  • Published : 2019.03.31

Abstract

Chemoresistance is the primary obstacle in the treatment of locally advanced and metastatic nasopharyngeal carcinoma (NPC). Recent evidence suggests that the transcription factor forkhead box M1 (FoxM1) is involved in chemoresistance. Our group previously confirmed that FoxM1 is overexpressed in NPC. In this study, we investigated the role of FoxM1 in cisplatin resistance of the cell lines 5-8F and HONE-1 and explored its possible mechanism. Our results showed that FoxM1 and NBS1 were both overexpressed in NPC tissues based on data from the GSE cohort (GSE12452). Then, we measured FoxM1 levels in NPC cells and found FoxM1 was overexpressed in NPC cell lines and could be stimulated by cisplatin. MTT and clonogenic assays, flow cytometry, ${\gamma}H2AX$ immunofluorescence, qRT-PCR, and western blotting revealed that downregulation of FoxM1 sensitized NPC cells to cisplatin and reduced the repair of cisplatin-induced DNA double-strand breaks via inhibition of the MRN (MRE11-RAD50-NBS1)-ATM axis, which might be related to the ability of FoxM1 to regulate NBS1. Subsequently, we demonstrated that enhanced sensitivity of FoxM1 knockdown cells could be reduced by overexpression of NBS1. Taken together, our data demonstrate that downregulation of FoxM1 could improve the sensitivity of NPC cells to cisplatin through inhibition of MRN-ATM-mediated DNA repair, which could be related to FoxM1-dependent regulation of NBS1.

Keywords

Cisplatin;FoxM1;MRN-ATM axis;Nasopharyngeal carcinoma;Resistance

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65, 87-108 https://doi.org/10.3322/caac.21262
  2. Al-Sarraf M, LeBlanc M, Giri PG et al (1998) Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 16, 1310-1317 https://doi.org/10.1200/JCO.1998.16.4.1310
  3. Yoshizaki T, Kondo S, Murono S et al (2015) Progress and controversy for the role of chemotherapy in nasopharyngeal carcinoma. Jpn J Clin Oncol 45, 244-247 https://doi.org/10.1093/jjco/hyu212
  4. Lee AW, Sze WM, Au JS et al (2005) Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience. Int J Radiat Oncol Biol Phys 61, 1107-1116 https://doi.org/10.1016/j.ijrobp.2004.07.702
  5. Lee AW, Poon YF, Foo W et al (1992) Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys 23, 261-270 https://doi.org/10.1016/0360-3016(92)90740-9
  6. Galluzzi L, Senovilla L, Vitale I et al (2012) Molecular mechanisms of cisplatin resistance. Oncogene 31, 1869-1883 https://doi.org/10.1038/onc.2011.384
  7. Goldstein M and Kastan MB (2015) The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med 66, 129-143 https://doi.org/10.1146/annurev-med-081313-121208
  8. Paull TT and Lee JH (2005) The Mre11/Rad50/Nbs1 complex and its role as a DNA double-strand break sensor for ATM. Cell Cycle 4, 737-740 https://doi.org/10.4161/cc.4.6.1715
  9. Frappart PO, Tong WM, Demuth I et al (2005) An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nat Med 11, 538-544 https://doi.org/10.1038/nm1228
  10. So S, Davis AJ and Chen DJ (2009) Autophosphorylation at serine 1981 stabilizes ATM at DNA damage sites. J Cell Biol 187, 977-990 https://doi.org/10.1083/jcb.200906064
  11. Lamarche BJ, Orazio NI and Weitzman MD (2010) The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett 584, 3682-3695 https://doi.org/10.1016/j.febslet.2010.07.029
  12. Laoukili J, Stahl M and Medema RH (2007) FoxM1: at the crossroads of ageing and cancer. Biochim Biophys Acta 1775, 92-102
  13. Koo CY, Muir KW and Lam EW (2012) FOXM1: From cancer initiation to progression and treatment. Biochim Biophys Acta 1819, 28-37 https://doi.org/10.1016/j.bbagrm.2011.09.004
  14. Zhou J, Wang Y, Wang Y et al (2014) FOXM1 modulates cisplatin sensitivity by regulating EXO1 in ovarian cancer. PLoS One 9, e96989 https://doi.org/10.1371/journal.pone.0096989
  15. Park YY, Jung SY, Jennings NB et al (2012) FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair. Carcinogenesis 33, 1843-1853 https://doi.org/10.1093/carcin/bgs167
  16. Chua MLK, Wee JTS, Hui EP and Chan ATC (2016) Nasopharyngeal carcinoma. Lancet 387, 1012-1024 https://doi.org/10.1016/S0140-6736(15)00055-0
  17. Kuo LJ and Yang LX (2008) Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo 22, 305-309
  18. Wang KMsd, Chen ZMsd, Long LMsd et al (2018) iTRAQ-based quantitative proteomic analysis of differentially expressed proteins in chemoresistant nasopharyngeal carcinoma. Cancer Biol Ther 19, 1-16 https://doi.org/10.1080/15384047.2017.1394554
  19. Bensouda Y, Kaikani W, Ahbeddou N et al (2011) Treatment for metastatic nasopharyngeal carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis 128, 79-85 https://doi.org/10.1016/j.anorl.2010.10.003
  20. Yu C, Chen L, Yie L et al (2015) Targeting FoxM1 inhibits proliferation, invasion and migration of nasopharyngeal carcinoma through the epithelialto-mesenchymal transition pathway. Oncol Rep 33, 2402-2410 https://doi.org/10.3892/or.2015.3834
  21. Jiang L, Wang P and Chen H (2014) Overexpression of FOXM1 is associated with metastases of nasopharyngeal carcinoma. Ups J Med Sci 119, 324-332 https://doi.org/10.3109/03009734.2014.960053
  22. San Filippo J, Sung P and Klein H (2008) Mechanism of eukaryotic homologous recombination. Annu Rev Biochem 77, 229-257 https://doi.org/10.1146/annurev.biochem.77.061306.125255
  23. Tauchi H, Kobayashi J, Morishima K et al (2002) Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. Nature 420, 93-98 https://doi.org/10.1038/nature01125
  24. Nestal de Moraes G, Bella L, Zona S, Burton MJ and Lam EW (2016) Insights into a critical role of the FOXO3a-FOXM1 axis in DNA damage response and genotoxic drug resistance. Curr Drug Targets 17, 164-177 https://doi.org/10.2174/1389450115666141122211549
  25. Rocha CRR, Silva MM, Quinet A, Cabral-Neto JB and Menck CFM (2018) DNA repair pathways and cisplatin resistance: an intimate relationship. Clinics (Sao Paulo) 73, e478s
  26. Salehan MR and Morse HR (2013) DNA damage repair and tolerance: a role in chemotherapeutic drug resistance. Br J Biomed Sci 70, 31-40 https://doi.org/10.1080/09674845.2013.11669927
  27. Jiang L, Wang P, Chen L and Chen H (2014) Down-regulation of FoxM1 by thiostrepton or small interfering RNA inhibits proliferation, transformation ability and angiogenesis, and induces apoptosis of nasopharyngeal carcinoma cells. Int J Clin Exp Pathol 7, 5450-5460
  28. Zheng J, Zhang C, Jiang L et al (2011) Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma. Mol Carcinog 50, 689-696 https://doi.org/10.1002/mc.20803
  29. Jiang L, Wu X, Wang P et al (2015) Targeting FoxM1 by thiostrepton inhibits growth and induces apoptosis of laryngeal squamous cell carcinoma. J Cancer Res Clin Oncol 141, 971-981 https://doi.org/10.1007/s00432-014-1872-3
  30. Ziebarth AJ, Nowsheen S, Steg AD et al (2013) Endoglin (CD105) contributes to platinum resistance and is a target for tumor-specific therapy in epithelial ovarian cancer. Clin Cancer Res 19, 170-182 https://doi.org/10.1158/1078-0432.CCR-12-1045

Acknowledgement

Supported by : Natural Science Foundation of China