Celecoxib induces cell apoptosis coupled with up-regulation of the expression of VEGF by a mechanism involving ER stress in human colorectal cancer cells

被引:24
作者
Du, Hansong [2 ]
Li, Wei [2 ]
Wang, Yu [1 ]
Chen, Sufang [1 ]
Zhang, Ying [1 ]
机构
[1] Huazhong Univ Sci & Technol, Dept Biochem & Mol Biol, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China
[2] Huazhong Univ Sci & Technol, Union Hosp, Dept Gastrointestinal Surg, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China
关键词
celecoxib; VEGF; endoplasmic reticulum stress; cell apoptosis; ENDOPLASMIC-RETICULUM STRESS; ENDOTHELIAL GROWTH-FACTOR; UNFOLDED PROTEIN RESPONSE; CYCLOOXYGENASE-2; INHIBITORS; BREAST-CANCER; COX-2; ANGIOGENESIS; INDUCTION; INCREASES; ANALOG;
D O I
10.3892/or.2011.1297
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Increasing evidence suggests that celecoxib, a COX-2 inhibitor with potent anticancer activity exerts its effects not only through COX-2, but also through COX-2-independent mechanisms. In the present study, we hypothesized that endoplasmic reticulum stress (ERS) is involved in the up-regulation of VEGF expression induced by celecoxib in colorectal cancer HCT116 cells and that ERS is a major mechanism by which celecoxib triggers tumor cell death in a COX-2-independent manner. HCT116 cells, which do not express COX-2, were cultured in the absence or presence of celecoxib. VEGF expression was detected by quantitative real-time RT-PCR and Western blotting. ERS triggered by celecoxib was determined by expression of ER chaperones and other markers. PBA (an inhibitor of ERS) and GRP78 overexpression were both used to prevent ERS. Cell apoptosis was evaluated by TUNEL assay and fluorescence activated cell sorting. In HCT116 cells, celecoxib increased VEGF production with time-course and dose-response curves similar to those observed for the increase of the ER chaperone, GRP78. CHOP, a marker of ERS involved in apoptosis, was also increased by celecoxib. Moreover, celecoxib promoted cell apoptosis. Both apoptosis and up-regulation of VEGF were prevented by protecting cells from ERS. Celecoxib induces cell apoptosis and up-regulation of VEGF in HCT116 cells via activation of the ERS response. Further studies are necessary to evaluate whether the combination of celecoxib with anti-VEGF agents is a promising therapeutic modality for cancer.
引用
收藏
页码:495 / 502
页数:8
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