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ESE-1/EGR-1 Pathway Plays a Role in Tolfenamic Acid-Induced Apoptosis in Colorectal Cancer Cells

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ESE-1/EGR-1 Pathway Plays a Role in Tolfenamic Acid-Induced Apoptosis in Colorectal Cancer Cells 3739 ESE-1/EGR-1 pathway plays a role in tolfenamic acid-induced apoptosis in colorectal cancer cells Seong-Ho Lee,1 Jae Hoon Bahn,1 cancer cells, and gene silencing using ESE-1 small Chang Kyoung Choi,1,2 Nichelle C. Whitlock,1 interfering RNA attenuated tolfenamic acid-induced EGR- Anthony E. English,2 Stephen Safe,3 1 expression and apoptosis. Overexpression of EGR-1 and Seung Joon Baek1 increased apoptosis and decreased bioelectrical imped- ance, and silencing of endogenous EGR-1 prevented 1Laboratory of Environmental Carcinogenesis, Department of tolfenamic acid-induced apoptosis. These results show Pathobiology, College of Veterinary Medicine, and 2Department of that activation of ESE-1 via enhanced nuclear transloca- Mechanical, Aerospace and Biomedical Engineering, College of tion mediates tolfenamic acid-induced EGR-1 expression, Engineering, University of Tennessee, Knoxville, Tennessee and 3Department of Veterinary Physiology and Pharmacology, Texas which plays a critical role in the activation of apoptosis. A&M University, College Station, Texas [Mol Cancer Ther 2008;7(12):3739–50] Introduction Abstract Epidemiologic studies have reported an inverse correlation Nonsteroidal anti-inflammatory drugs (NSAIDs) are between colon cancer incidence and the use of nonsteroidal known to prevent colorectal tumorigenesis. Although anti-inflammatory drugs (NSAIDs; ref. 1). As a result, the antitumor effects of NSAIDs are mainly due to inhibition regular use of NSAIDs as a chemopreventive strategy for of cyclooxygenase activity, there is increasing evidence colorectal cancer is now generating a great deal of interest that cyclooxygenase-independent mechanisms may also because NSAIDs inhibit cyclooxygenase (COX) and pros- play an important role. The early growth response-1 taglandin biosynthesis, a pathway strongly associated with (EGR-1) gene is a member of the immediate-early gene colorectal carcinogenesis (2). NSAIDs induce cell cycle family and has been identified as a tumor suppressor arrest and apoptosis during different stages of colorectal gene. Tolfenamic acid is a NSAID that exhibits anticancer tumorigenesis (3–5) and inhibit angiogenesis, invasion, activity in a pancreatic cancer model. In the present study, and metastasis in vivo (6, 7). we investigated the anticancer activity of tolfenamic Tolfenamic acid has been broadly used for treatment of acid in human colorectal cancer cells. Tolfenamic acid migraines and has shown fewer upper gastrointestinal treatment inhibited cell growth and induced apoptosis as side effects than other NSAIDs (8). There is recent measured by caspase activity and bioelectric impedance. evidence showing that tolfenamic acid also affects Tolfenamic acid induced EGR-1 expression at the tran- metastasis and tumorigenesis in pancreatic cancer models scription level, and analysis of the EGR-1 promoter (9, 10). Tolfenamic acid reduces the expression of vascular showed that a putative ETS-binding site, located at endothelial growth factor and its receptor (9, 10), which are À À 400 and 394 bp, was required for activation by mediated in part by down-regulation of specificity proteins tolfenamic acid. The electrophoretic mobility shift assay (Sp). Like other NSAIDs, tolfenamic acid acts by inhibiting and chromatin immunoprecipitation assay confirmed that COX and prostaglandin biosynthesis; however, the this sequence specifically bound to the ETS family protein molecular basis for induction of apoptosis and the scope epithelial-specific ETS-1 (ESE-1) transcription factor. of its action in colorectal cancer has not been reported. Tolfenamic acid also facilitated translocation of endoge- One potential molecular target is early growth response-1 nous and exogenous ESE-1 to the nucleus in colorectal (EGR-1), an immediate-early gene encoding a zinc finger transcription factor; EGR-1regulates the expression of genes involved in growth control or survival (11). The EGR-1 gene is stimulated by many extracellular signaling Received 6/13/08; revised 9/5/08; accepted 9/23/08. molecules including cytotoxic metabolites, hormones, Grant support: American Cancer Society grant CNE-111611, NIH grant RO1CA108975, and University of Tennessee Center of Excellence in growth factors, and neurotransmitters. The growth- Livestock Diseases and Human Health (S.J. Baek) and National Science promoting activity by EGR-1has been observed in various Foundation CAREER award BES-0238905 (A.E. English). humancancermodelssuchasprostate(12),skin(13),and The costs of publication of this article were defrayed in part by the kidney (14). Various growth factors target the EGR-1 gene payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to and mediate the mitogenic signaling cascade (15). Despite indicate this fact. the discovery of EGR-1as a growth-promoting protein, Requests for reprints: Seung Joon Baek, Laboratory of Environmental several reports have described EGR-1as a proapoptotic Carcinogenesis, Department of Pathobiology, College of Veterinary protein. Indeed, EGR-1is down-regulated in neoplasia Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996-4542. Phone: 865-974-8216; Fax: 865-974-5616. and an array of tumor cell lines (16), and constitutive E-mail: [email protected] expression of EGR-1suppressed growth and transforma- Copyright C 2008 American Association for Cancer Research. tion in tumor cells (17). Recently, we and others reported doi:10.1158/1535-7163.MCT-08-0548 that EGR-1 acts as a proapoptotic gene in human colorectal Mol Cancer Ther 2008;7(12). December 2008 Downloaded from mct.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. 3740 Proapoptotic Effect of Tolfenamic Acid cancer cells. EGR-1is a target of chemopreventive com- internal deletion mutant clones for ETS-binding site (EBS), pounds including NSAIDs, LY294002, peroxisome prolif- Sp1, SRF, and C/EBP of the EGR-1 promoter were erator-activated receptor g ligands (18–21), and dietary generated with the pEGR1-1260/+35 wild-type clone compounds such as epicatechin gallate and 1,1-bis(3¶- using the QuickChange II site-directed Mutagenesis Kit indolyl)-1-(p-substituted phenyl) methanes (22–24). In (Stratagene). addition, EGR-1mediates several proapoptotic proteins, Cell Culture and Treatment including p53, phosphatase and tensin homologue, acti- Human colorectal carcinoma cell lines HCT-116, SW480, vating transcription factor 3, and NSAID-activated gene-1 LoVo, and HT-29 were purchased from American Type (NAG-1), which appear to play a critical role in mediating Culture Collection. HCT-116 and HT-29 cells were main- apoptosis in human colorectal cancer cells (18–21, 25, 26). tained in McCoy’s 5A medium, and SW480 and LoVo cells Thus, the proapoptotic activity of EGR-1may depend on were maintained in RPMI 1640 and Ham’s F-12 medium, the cell type and the nature of the cytotoxic stimulus. respectively. All media were supplemented with 10% fetal The current study was done to elucidate whether bovine serum, 100 units/mL penicillin, and 100 Ag/mL tolfenamic acid affects human colorectal tumorigenesis. streptomycin. Cells were incubated at 37jCundera Here, we report, for the first time, that tolfenamic acid humidified atmosphere of 5% CO2 until cells were 70% to suppresses proliferation and induces apoptosis in human 80% confluent. The cells were then treated with different colorectal cancer cells through induction of a novel concentrations of tolfenamic acid at different time points as pathway that involves increased nuclear accumulation of indicated in the figure legends. epithelial-specific ETS-1(ESE-1)transcription factor, Cell Proliferation which in turn activates EGR-1. Tolfenamic acid-induced A cell proliferation assay was done using the CellTiter EGR-1expression results in the induction of apoptosis, 96 Aqueous One Solution Cell Proliferation Assay (Prom- which is mediated in part by activation of the proapop- ega) as described previously (28). Briefly, cells were seeded totic protein NAG-1. at the concentration of 2,000 per well in 96-well tissue culture plates in four replicates and maintained overnight. The cells were then treated with 0, 1, 5, 10, 20, 30, and Material and Methods 50 Amol/L tolfenamic acid. At 0, 24, and 48 h after Materials treatment, 20 AL CellTiter96 Aqueous One solution was Tolfenamic acid and SC-560 were purchased from added to each well, and the plate was incubated for 1h at Cayman Chemical, and 5,5-dimethyl-3-(3-fluorophenyl)- 37jC. Absorbance at 490 nm was recorded in an ELISA 4-(4-methylsulphonyl)phenyl-2(5H)-furanone was de- plate reader (Bio-Tek Instruments). scribed previously (20). All other NSAIDs were purchased Caspase-3/7 Enzyme Activity from Sigma-Aldrich. Antibodies for EGR-1 (sc-110), ESE-1 Apoptosis was measured using Apo-ONE Homogeneous (sc-17306), actin (sc-1615), control small interfering RNA Caspase-Glo-3/7 Assay kit (Promega) according to the (siRNA; sc-37007), and ESE-1 siRNA (sc-37851) were manufacturer’s protocol. After harvest of the cells using purchased from Santa Cruz Biotechnology, and antibody radioimmunoprecipitation assay buffer containing protease for poly(ADP-ribose) polymerase (PARP) was purchased inhibitors, the cell lysates (50 Ag protein) in 50 AL volume from Cell Signaling. Antibodies for V5 (R960-25) and were mixed with 50 AL Caspase-Glo-3/7 reagent in 96-well Sp1(07-124)were purchased from Invitrogen and Upstate plates and incubated at room temperature in the dark
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