title: Celecoxib induces apoptosis but up-regulates VEGF via endoplasmic reticulum stress in human colorectal cancer in vitro and in vivo.
abstract: OBJECTIVE
  In our previous study, we found that celecoxib, a kind of COX-2 inhibitor, led to cell apoptosis while up-regulating the expression of vascular endothelial growth factor (VEGF) in colorectal cancer HCT116 cells (COX-2 deficient), and endoplasmic reticulum (ER) stress was involved in the mechanism. Thus, we would like to explore whether these results are universal for other colorectal cancer cells, especially for COX-2-expressing ones, and whether the results in vitro and in vivo are matched.
  
  
  METHODS
  HT29 cells (COX-2 expressing) were treated with celecoxib under different conditions to evaluate cell apoptosis, VEGF expression and the activation of ER stress. HT29 and HCT116 xenograft tumor models were established to evaluate anti-tumor effects and verify the experiment results we obtained in vitro.
  
  
  RESULTS
  Celecoxib (≥60 µM) up-regulated the expression of ER stress markers (GRP78 and CHOP) and induced cell apoptosis accompanying with a correlated increased expression of VEGF in HT29 cells. Celecoxib-induced gene expression and cell apoptosis were inhibited by an ER stress inhibitor, PBA. In xenograft models, celecoxib treatment inhibited tumor growth with increased GRP78 and VEGF, which was consistent with the results in vitro.
  
  
  CONCLUSIONS
  Celecoxib, both in vitro and in vivo, induced apoptosis of colorectal cancer cells but increased the VEGF levels at the same time in a COX-2-independent manner, namely by activating ER stress. The increased VEGF would impair the effect of celecoxib and bring drug resistant; hence, the optimal schedule of the combination of celecoxib with anti-VEGF drugs needs to be explored.
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Bingfei
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Infectious Disease, Renmin Hospital, Hubei University of Medicine, Shiyan, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430030, People's Republic of China. u200910446@hust.edu.cn.
authors.forename: Hansong
authors.initials: H
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D000068579:Celecoxib
keywords: Apoptosis; Celecoxib; ER stress; Human colorectal cancer; VEGF