title: COX-2 promotes breast cancer cell radioresistance via p38/MAPK-mediated cellular anti-apoptosis and invasiveness.
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.
authors.affiliation: Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
authors.forename: Fengjuan
authors.initials: F
authors.lastname: Lin
authors.forename: Jianmin
authors.initials: J
authors.lastname: Luo
authors.forename: Wen
authors.initials: W
authors.lastname: Gao
authors.forename: Jiong
authors.initials: J
authors.lastname: Wu
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Shao
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Wang
authors.forename: Jiao
authors.initials: J
authors.lastname: Meng
authors.forename: Zhouluo
authors.initials: Z
authors.lastname: Ou
authors.forename: Gong
authors.initials: G
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor / Q000528:radiation effects; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000502:physiology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011836:Radiation Tolerance; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases