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Tumor Biology

, Volume 34, Issue 5, pp 2817–2826 | Cite as

COX-2 promotes breast cancer cell radioresistance via p38/MAPK-mediated cellular anti-apoptosis and invasiveness

  • Fengjuan Lin
  • Jianmin Luo
  • Wen Gao
  • Jiong Wu
  • Zhimin Shao
  • Ziliang Wang
  • Jiao Meng
  • Zhouluo Ou
  • Gong Yang
Research Article

Abstract

Radioresistance is one of the major barriers to improve the survival rate of breast cancer patients. Cyclooxygenase 2 (COX-2) is usually overexpressed in highly invasive and metastatic breast cancer, which may indicate an association with breast cancer radioresistance. The function role of COX-2 was investigated by using a radioresistant breast cancer cell line MDA-MB-231/RR10 and its parental cell line MDA-MB-231 cells before or after COX-2 was silenced by a specific small hairpin RNA (shRNA). The cell proliferation, migration, invasion, colony formation, and apoptosis were measured by CCK-8, scratch-wound, transwell, clone formation assay, and flow cytometry. Protein and mRNA expression were analyzed by Western blot and quantitative reverse transcriptase-polymerase chain reaction. COX-2 is upregulated in MDA-MB-231/RR10 cells compared with in MDA-MB-231 cells, and silencing of COX-2 expression by shRNA in MDA-MB-231/RR10 cells decreases the expression of Bcl-2 and Bcl-XL, but increases the proapoptotic protein BAK, leading to the increased apoptosis following treatment with γ-irradiation in comparison with those in control cells. Silencing of COX-2 also increases the expression of β-catenin and E-cadherin, two anti-invasion proteins, resulting in reduced cell migration and invasion tested by transwell chambers and wound-healing assays. Further study demonstrated that COX-2-induced radioresistance is negatively regulated through the phosphorylation of p38 at Tyr182, and that the phosphorylation of p38 induced by TNF-alpha reduces the expression of Bcl-2, BCL-XL, but increases β-catenin and E-cadherin, leading to the decreased invasiveness of cells. Our data suggest that COX-2, p38, Bcl-2, Bcl-XL, β-catenin, and E-cadherin may be considered as potential therapeutic targets against radioresistant breast cancer.

Keywords

COX-2 Radioresistance Breast cancer p38 MAPK 

Notes

Acknowledgments

Z. Ou was supported by National Natural Science Foundation of China (81172506) and by the Shanghai Committee of Science and Technology, China (grant no. 12DZ2260100); G. Yang was supported by Doctoral Fund of Ministry of Education of China (20120071110079), by Shanghai Pujiang Program (11PJ1402200) from Shanghai Municipal Government of China, and by National Nature Science Foundation of China (91129721).

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Fengjuan Lin
    • 1
    • 2
    • 4
  • Jianmin Luo
    • 2
    • 4
  • Wen Gao
    • 1
    • 3
    • 4
  • Jiong Wu
    • 2
    • 4
  • Zhimin Shao
    • 2
    • 4
  • Ziliang Wang
    • 1
    • 4
  • Jiao Meng
    • 1
    • 4
  • Zhouluo Ou
    • 2
    • 4
  • Gong Yang
    • 1
    • 4
  1. 1.Cancer Research LaboratoryFudan University Shanghai Cancer CenterShanghaiChina
  2. 2.Breast Cancer Institute and Key Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CenterShanghaiChina
  3. 3.Department of Gynecological OncologyFudan University Shanghai Cancer CenterShanghaiChina
  4. 4.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina

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