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Fenofibrate Increases Radiosensitivity in Head and Neck Squamous Cell Carcinoma via Inducing G2/M Arrest and Apoptosis

  • Liu, Jia (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Ge, Yang-Yang (Department of Radiation Oncology, The Affiliated Tumor Hospital of Nantong University) ;
  • Zhu, Hong-Cheng (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Yang, Xi (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Cai, Jing (Department of Radiation Oncology, The Affiliated Tumor Hospital of Nantong University) ;
  • Zhang, Chi (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Lu, Jing (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Zhan, Liang-Liang (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Qin, Qin (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Yang, Yan (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Yang, Yue-Hua (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Zhang, Hao (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Chen, Xiao-Chen (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Liu, Zhe-Ming (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University) ;
  • Ma, Jian-Xin (Department of Radiation Oncology, the Second People's Hospital of LianYungang, Lianyungang Hospital Affiliated to Bengbu Medical College) ;
  • Cheng, Hong-Yan (Department of General Internal Medicine, The First Affiliated Hospital of Nanjing Medical University) ;
  • Sun, Xin-Chen (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University)
  • Published : 2014.08.30

Abstract

Radiation therapy is an important treatment for head and neck squamous cell carcinoma (HNSCC). However, how to promote radiation sensitivity in HNSCC remains a challenge. This study aimed to investigate the radiosensitizing effects of fenofibrate on HNSCC and explore the underlying mechanisms. HNSCC cell lines CNE-2 and KB were subjected to ionizing radiation (IR), in the presence or absence of fenofibrate treatment. Cell growth and survival, apoptosis and cell cycle were evaluated. In addition, CNE-2 cells were xenografted into nude mice and subjected to IR and/or fenofibrate treatment. The expression of cyclinB and CDK1 was detected by Western blotting. Our results showed that fenofibrate efficiently radiosensitized HNSCC cells and xenografts in mice, and induced apoptosis and G2/M arrest via reducing the activity of the CDK1/cyclinB1 kinase complex. These data suggest that fenofibrate could be a promising radiosensitizer for HNSCC radiotherapy.

Keywords

Fenofibrate;HNSCC;cell cycle;radiotherapy

References

  1. Akervall J, Nandalur S, Zhang J, et al (2014). A novel panel of biomarkers predicts radioresistance in patients with squamous cell carcinoma of the head and neck. Eur J Cancer, 50, 570-81. https://doi.org/10.1016/j.ejca.2013.11.007
  2. Balfour JA, McTavish D, Heel RC (1990). Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia. Drugs, 40, 260-90. https://doi.org/10.2165/00003495-199040020-00007
  3. Banjerdpongchai R, Khaw-On P, Ristee C, Pompimon W (2013). 6, 8-dihydroxy-7-methoxy-1-methyl-azafluorenone induces caspase-8- and -9-mediated apoptosis in human cancer cells. Asian Pac J Cancer Prev, 14, 2637-41. https://doi.org/10.7314/APJCP.2013.14.4.2637
  4. Cho HJ, Oh YJ, Han SH, et al (2013). Cdk1 protein-mediated phosphorylation of receptor-associated protein 80 (RAP80) serine 677 modulates DNA damage-induced G2/M checkpoint and cell survival. J Biol Chem, 288, 3768-76. https://doi.org/10.1074/jbc.M112.401299
  5. Cui YH, Liang HJ, Zhang QQ, et al (2012). Radiosensitivity enhancement by arsenic trioxide in conjunction with hyperthermia in the EC-1 esophageal carcinoma cell line. Asian Pac J Cancer Prev, 13, 1693-7. https://doi.org/10.7314/APJCP.2012.13.4.1693
  6. Cariello NF, Romach EH, Colton HM, et al (2005). Gene expression profiling of the PPAR-alpha agonist ciprofibrate in the cynomolgus monkey liver. Toxicol Sci, 88, 250-64. https://doi.org/10.1093/toxsci/kfi273
  7. Grabacka M, Plonka PM, Urbanska K, Reiss K (2006). Peroxisome proliferator-activated receptor alpha activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt. Clin Cancer Res, 12, 3028-36. https://doi.org/10.1158/1078-0432.CCR-05-2556
  8. Hematulin A, Meethang S, Ingkaninan K, et al (2012). Derris scandens Benth extract potentiates radioresistance of Hep- 2 laryngeal cancer cells. Asian Pac J Cancer Prev, 13, 1289-95. https://doi.org/10.7314/APJCP.2012.13.4.1289
  9. Herscher LL, Cook J (1999). Taxanes as radiosensitizers for head and neck cancer. Curr Opin Oncol, 11, 183-6. https://doi.org/10.1097/00001622-199905000-00008
  10. Joe Y, Do MH, Seo E, et al (2010). Fenofibrate antagonizes Chk2 activation by inducing Wip1 expression: implications for cell proliferation and tumorigenesis. Life Sci, 86, 716-21. https://doi.org/10.1016/j.lfs.2010.03.006
  11. Khan M, Rasul A, Yi F, et al (2011). Jaceosidin induces p53- dependent G2/M phase arrest in U87 glioblastoma cells. Asian Pac J Cancer Prev, 12, 3235-8.
  12. Li XM, Di B, Shang YD, et al (2013). Value of postoperative radiation therapy for regional control after dissection in head and neck squamous cell carcinoma cases. Asian Pac J Cancer Prev, 14, 4273-8. https://doi.org/10.7314/APJCP.2013.14.7.4273
  13. Liang H, Kowalczyk P, Junco JJ, et al (2013). Differential Effects on Lung Cancer Cell Proliferation by Agonists of Glucocorticoid and PPARalpha Receptors. Mol Carcinog, 53, 753-63.
  14. Li T, Zhang Q, Zhang J, et al (2014). Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-kappaB pathway. BMC Cancer, 14, 96. https://doi.org/10.1186/1471-2407-14-96
  15. Lindqvist A, van Zon W, Karlsson Rosenthal C, Wolthuis RM (2007). Cyclin B1-Cdk1 activation continues after centrosome separation to control mitotic progression. PLoS Biol, 5, 123. https://doi.org/10.1371/journal.pbio.0050123
  16. Morse E, Selim E, Cunard R (2009). PPARalpha ligands cause lymphocyte depletion and cell cycle block and this is associated with augmented TRB3 and reduced Cyclin B1 expression. Mol Immunol, 46, 3454-61. https://doi.org/10.1016/j.molimm.2009.08.008
  17. Parkin DM, Bray F, Ferlay J, et al (2005). Global cancer statistics, 2002. CA Cancer J Clin, 55, 74-108. https://doi.org/10.3322/canjclin.55.2.74
  18. Pawlik TM, Keyomarsi K (2004). Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys, 59, 928-42. https://doi.org/10.1016/j.ijrobp.2004.03.005
  19. Ragin CC, Modugno F, Gollin SM (2007). The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res, 86, 104-14. https://doi.org/10.1177/154405910708600202
  20. Saidi SA, Holland CM, Charnock-Jones DS, Smith SK (2006). In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer. Mol Cancer, 5, 13. https://doi.org/10.1186/1476-4598-5-13
  21. Sun HJ, Meng LY, Shen Y, et al (2013). S-benzyl-cysteinemediated cell cycle arrest and apoptosis involving activation of mitochondrial-dependent caspase cascade through the p53 pathway in human gastric cancer SGC-7901 cells. Asian Pac J Cancer Prev, 14, 6379-84. https://doi.org/10.7314/APJCP.2013.14.11.6379
  22. Urbanska K, Pannizzo P, Grabacka M, et al (2008). Activation of PPARalpha inhibits IGF-I-mediated growth and survival responses in medulloblastoma cell lines. Int J Cancer, 123, 1015-24. https://doi.org/10.1002/ijc.23588
  23. Wilk A, Urbanska K, Grabacka M, et al (2012). Fenofibrateinduced nuclear translocation of FoxO3A triggers Bimmediated apoptosis in glioblastoma cells in vitro. Cell Cycle, 11, 2660-71. https://doi.org/10.4161/cc.21015
  24. Watanabe M, Sowa Y, Yogosawa M, Sakai T (2013). Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells. Cancer Sci, 104, 687-93. https://doi.org/10.1111/cas.12139
  25. Zhang C, Yang X, Zhang Q, et al (2014). Berberine radiosensitizes human nasopharyngeal carcinoma by suppressing hypoxiainducible factor-1alpha expression. Acta Otolaryngol, 134, 185-92. https://doi.org/10.3109/00016489.2013.850176
  26. Zhao H, Zhu C, Qin C, et al (2013). Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP. Biochem Biophys Res Commun, 432, 320-25. https://doi.org/10.1016/j.bbrc.2013.01.105
  27. Zak Z, Gelebart P, Lai R (2010). Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFalpha/NF-kappaB signaling axis. Leukemia, 24, 1476-86. https://doi.org/10.1038/leu.2010.117
  28. Zhou J, Luo YH, Wang JR, et al (2013). Gambogenic acid induction of apoptosis in a breast cancer cell line. Asian Pac J Cancer Prev, 14, 7601-5. https://doi.org/10.7314/APJCP.2013.14.12.7601
  29. Zhai X, Yang Y, Wan J, et al (2013). Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells. Oncol Rep, 30, 2983-91.

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