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The Involvement of Endoplasmic Reticulum Stress in the Suppression of Colorectal Tumorigenesis by Tolfenamic Acid

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The Involvement of Endoplasmic Reticulum Stress in the Suppression of Colorectal Tumorigenesis by Tolfenamic Acid Published OnlineFirst October 8, 2013; DOI: 10.1158/1940-6207.CAPR-13-0220 Cancer Prevention Research Article Research The Involvement of Endoplasmic Reticulum Stress in the Suppression of Colorectal Tumorigenesis by Tolfenamic Acid Xiaobo Zhang1,2, Seong-Ho Lee3, Kyung-Won Min2, Michael F. McEntee2, Jin Boo Jeong3, Qingwang Li1, and Seung Joon Baek2 Abstract The nonsteroidal anti-inflammatory drug tolfenamic acid has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which tolfenamic acid exerts its antitumorigenic effect remains unclear. Previous data from our group and others indicate that tolfenamic acid alters expression of apoptosis- and cell-cycle arrest–related genes in colorectal cancer cells. þ Here, we show that tolfenamic acid markedly reduced the number of polyps and tumor load in APCmin/ mice, accompanied with cyclin D1 downregulation in vitro and in vivo. Mechanistically, tolfenamic acid promotes endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) signaling pathway, of which PERK-mediated phosphorylation of eukaryotic translation initiation factor 2a (eIF2a) induces the repression of cyclin D1 translation. Moreover, the PERK-eIF2a-ATF4 branch of the UPR pathway plays a role in tolfenamic acid-induced apoptosis in colorectal cancer cells, as silencing ATF4 attenuates tolfenamic acid-induced apoptosis. Taken together, these results suggest ER stress is involved in tolfenamic acid-induced inhibition of colorectal cancer cell growth, which could contribute to antitumor- igenesis in a mouse model. Cancer Prev Res; 6(12); 1–11. Ó2013 AACR. Introduction and has received much attention since the inhibition of Colorectal cancer is the third-leading cause of cancer- COX-2 activity produces adverse effects (5). related death in the United States (1). Taking nonsteroidal Tolfenamic acid is a conventional NSAID that has been anti-inflammatory drugs (NSAID) has been associated with long used for treatment of migraines. Compared with the a reduced risk of colorectal tumorigenesis in epidemiologic other NSAIDs, tolfenamic acid exhibits fewer upper gastro- studies (2), and a large amount of evidence from cell culture intestinal side effects (6). Increasing evidence has shown and animal studies has also shown that NSAID treatments that tolfenamic acid also suppresses tumorigenesis in sev- can inhibit growth of cancer cells and tumors (3). Many eral cancer models (7–12), and that this suppression seems mechanisms have been proposed to elucidate the effect of to be independent of COX inhibition. For example, sup- NSAIDs in antitumorigenesis (4). One such proposed pression of specificity proteins Sp1, Sp3, and Sp4, and their mechanism is through the inhibition of COX-2, which is target genes, has been considered to contribute to tolfe- overexpressed in human tumors and plays a role in carci- namic acid-induced anticancer activity (7). Previous results nogenesis. However, a COX-independent function of from our lab also indicate that tolfenamic acid inhibits cell NSAIDs also plays an important role in antitumorigenesis proliferation and induces apoptosis in human colorectal cancer cells, which is in part mediated by the induction of the tumor suppressor proteins NAG-1 and ATF3 (13, 14). These data suggest that tolfenamic acid could exert antican- Authors' Affiliations: 1College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China; 2Department of Bio- cer activity through various molecular mechanisms, and medical and Diagnostic Sciences, College of Veterinary Medicine, Univer- prompted us to further investigate the additional molecular 3 sity of Tennessee, Knoxville, Tennessee; and Department of Nutrition and mechanisms by which tolfenamic acid induces anticancer Food Science, University of Maryland, College Park, Maryland activity. Note: Supplementary data for this article are available at Cancer Prevention Cyclin D1, an oncogenic protein, is often overexpressed Research Online (http://cancerprevres.aacrjournals.org/). in various cancer cells and tumor tissues. The activated Corresponding Authors: Seung Joon Baek, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of cyclin D1-CDK4/6 complex phosphorylates Rb protein and Tennessee, 2407 River Drive, Knoxville, TN 37996-4542. Phone: 865-974- subsequently induces the expression of E2F-target genes 8216; Fax: 865-974-5616; E-mail: [email protected]; Qingwang Li, College that are necessary for DNA synthesis (15). In a recent study, of Animal Science and Technology, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, People's Republic of China. Phone: 86- cyclin D1 was also shown to play a role in DNA repair 137-0912-9117; Fax: 86-029-8709-2164; E-mail: through binding to DNA repair proteins, such as BRCA2 [email protected] and RAD51 (16), indicating an extra role of cyclin D1. A doi: 10.1158/1940-6207.CAPR-13-0220 variety of compounds, including NSAIDs, have been docu- Ó2013 American Association for Cancer Research. mented to mediate cyclin D1 degradation and cell growth www.aacrjournals.org OF1 Downloaded from cancerpreventionresearch.aacrjournals.org on September 23, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst October 8, 2013; DOI: 10.1158/1940-6207.CAPR-13-0220 Zhang et al. inhibition (17). It has been reported that tolfenamic acid PERK, and PARP were from Cell Signaling Technology; and also downregulated cyclin D1 expression in esophageal and antibody for HA tag was from GenScript. Control siRNA breast cancer cells (8, 9); however, the detailed molecular (#6201) and siRNA for PERK (#9024) were obtained from mechanism(s) is not clear. Elucidation of the molecular Cell Signaling Technology. siATF4 (sc-35112) was purchased mechanism(s) underlying cyclin D1 downregulation by from Santa Cruz Biotechnology. tolfenamic acid would be beneficial to further understand the antitumorigenic activity of tolfenamic acid, and to Cell culture develop novel derivatives, which could exert more pro- Human cancer cell lines (HCT-116, HT-29, SW480, nounced anticancer effects. LoVo, Caco-2, A549, PC-3, and AsPC-1) were purchased Endoplasmic reticulum (ER) stress inhibits cyclin D1 from American Type Culture Collection (ATCC). ATCC translation and cell-cycle progression (18). Moreover, ER tests the authenticity of these cell lines using short tandem stress initiates apoptosis by activating transcription factor 4 repeat analyses. HCT-116 and HT-29 cells were maintained (ATF4)-dependent C/EBP homologous transcription factor in McCoy’s 5A medium (Bio Whittaker). SW480, A549, (CHOP), apoptosis signal-regulating kinase 1 (ASK1), and PC-3, and AsPC-1 cells were maintained in RPMI-1640 caspase-12 (19). Interestingly, two ER stress-inducible genes medium (Mediatech). Caco-2 and LoVo cells were kept in (EGR1 and ATF3) have been previously identified as the Eagle’s minimum essential medium and Ham’s F12 medi- anticancer targets of tolfenamic acid in colon cancer (13, um (HyClone), respectively. All cells were cultured in 14). Thus, ER stress could be involved in tolfenamic acid- media supplemented with 10% FBS, 100 U/mL penicillin, mediated cancer cell growth suppression. Indeed, some and 100 mg/mL streptomycin in a 5% CO2 atmosphere at NSAIDs like indomethacin and celecoxib have been shown 37C. to trigger ER stress response (20, 21). In contrast, diclofenac blocked ER stress-induced apoptosis in SH-SY5Y cells (22), Plasmid, mutagenesis, and transient transfection and pranoprofen also suppressed ER stress-induced glu- The pRcCMV-cyclin D1-HA plasmid was generously cose-regulated protein 78 (GRP78) and CHOP expression provided by Dr. E. Dmitrovsky (Department of Pharma- (23). Therefore, how ER stress is involved in tolfenamic cology and Toxicology, Dartmouth Medical School, Han- acid’s effect on cell growth remains unclear and needs to be over, NH; ref. 25). The pCMV-cyclin D1 and ubiquitin further elucidated. (Ub)-HA were gifts from Dr. Richard G. Pestell (Kimmel In the current studies, we first evaluated the chemo- Cancer Center, Thomas Jefferson University, Philadel- preventive effect of tolfenamic acid in a mouse model of phia, PA). Cyclin D1 transversion from threonine to colorectal cancer. As a result, we found that tolfenamic acid alanine at the 286 amino acid position was generated þ inhibited polyp formation in APCmin/ mice, along with a using the QuickChange site-directed mutagenesis kit dramatic decrease in cyclin D1 expression in tumors. Con- (Strategene) according to the manufacturer’s protocol. sistently, we have also shown that tolfenamic acid down- ATF4 expression construct was purchased from OriGene, regulates cyclin D1 expression in different cancer cells in and p5xATF6-GL3 luciferase reporter construct (plasmid vitro, which is associated with the increase in Rb activity. We #11976) was obtained from Addgene (26). Transient further investigated the underlying mechanism, showing transfection was carried out using TransIT-2020 transfec- that tolfenamic acid repressed cyclin D1 translation through tion reagent (Mirus Bio LLC) according to the manufac- activation of the ER stress-mediated unfolded protein turer’s protocol. For luciferase assay, cells were seeded in responses (UPR) pathway. In addition, ER stress played a 12-well plates at a density of 1.0 Â 105 cells per well. After role in tolfenamic acid-induced apoptosis in colorectal transfection with 1 mg
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