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Tolfenamic Acid Increases EGR‐1 Expression through a PKC/ERK Dependent Pathway in Human Colorectal Cancer Cells
Author(s) -
Lee SeongHo,
Whitlock Nichelle C,
Choi Chang Kyoung,
English Anthony E,
Safe Stephen H,
Baek Seung J
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.649.3
Subject(s) - apoptosis , transactivation , carcinogenesis , colorectal cancer , cancer research , mapk/erk pathway , transfection , cancer , chemistry , protein kinase c , microbiology and biotechnology , ectopic expression , cancer cell , kinase , biology , medicine , transcription factor , biochemistry , gene
Considerable evidence indicates that the use of non‐steroidal anti‐inflammatory drugs (NSAIDs) reduces the mortality of colorectal cancer in a cyclooxygenase (COX)‐independent manner. Tolfenamic acid (TA) has been selected as a potent chemopreventive agent for cancer therapy because of its inhibitory effect on tumorigenesis in pancreatic cancer models. In the present study, we sought to the anti‐cancer effect of TA in human colorectal cancer. The mechanisms by which TA affects anti‐tumorigenesis involve the induction of the proapoptotic protein EGR‐1 in human colorectal cancer cells. TA treatment inhibited cell proliferation and induced apoptosis in HCT‐116 cells. Electrical impedance study showed that TA resulted in a decrease of the normalized impedance components which reflect increasing numbers of apoptotic cells. Ectopic expression of EGR‐1 increased apoptosis, and siRNA of EGR‐1 reduced TA‐induced apoptosis. TA treatment induced approximately 5.5‐fold induction of luciferase activity of EGR‐1 promoter. Subsequently, the results of the luciferase assay using internal deletion clones showed that the EBS and CREB/ATF binding sites in the EGR‐1 promoter are required for TA‐induced EGR‐1 transactivation. Experiments using kinase inhibitors and siRNA transfection implied the involvement of the PKC/ERK pathway in TA‐induced EGR‐1 expression. These results demonstrate a role of EGR‐1 in TA‐induced anti‐tumorigenesis in human colorectal cancer cells.