Altered Gene Expression Profiles Define Pathways in Colorectal Cancer Cell Lines Affected by Celecoxib

Abstract

It is well established that celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2) and a tested chemopreventive agent, has several COX-2 -independent activities. In an attempt to better understand COX-2 -independent molecular mechanisms underlying the chemopreventive activity of celecoxib, we did global transcription profiling of celecoxib-treated COX-2 -positive and COX-2 -deficient colorectal cancer cell lines. Celecoxib treatment resulted in significantly altered expression levels of over 1,000 to 3,000 transcripts in these cell lines, respectively. A pathway/functional analysis of celecoxib-affected transcripts, using Gene Ontology and Biocarta Pathways and exploring biological association networks, revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes, including metabolism, cell proliferation, apoptotic signaling, cell cycle check points, lymphocyte activation, and signaling pathways. Among these processes, cell proliferation and apoptotic signaling consistently ranked as the highest-scoring Gene Ontology terms and Biocarta Pathways in both COX-2 expresser and nonexpresser cell lines. Altered expression of many of the genes by celecoxib was confirmed by quantitative PCR and at the protein level by Western blotting. Many novel genes emerged from our analysis of global transcription patterns that were not previously reported to be affected by celecoxib. In the future, in-depth work on selected genes will determine if these genes may serve as potential molecular targets for more effective chemopreventive

Non-Steroidal Anti-Inflammatory Drugs, DNA Repair and Cancer

“…Microarray analysis of the colorectal cancer cell line HT-29 treated with 1mM and 5mM aspirin showed an up-regulation of GADD45α (Yin et al, 2006). Further to this, microarray analysis also shows GADD45 gene expression to be upregulated by NS-398 (Huang et al, 2006) and celecoxib (Fatima et al, 2008) in colorectal cancer cells and by ibuprofen in human gastric adenocarcinoma cell line (Bonelli et al, 2010). Suppression of GADD45α expression confers resistance to sulindac and indomethacin induced gastric mucosal injury and apoptosis (Chiou et al, 2010) .…”

“…PCNA gene expression has been shown to be up-regulated by ibuprofen treatment of a human gastric adenocarcinoma cell line (Bonelli et al, 2010), and also in the human hepatocellular carcinoma cell line HepG2 treated with 25mM vanillin (Cheng et al, 2007). In contrast, down-regulation of PCNA gene expression has been reported in colorectal cancer cell lines treated with celecoxib suggesting that these compounds may modulate cell cycle regulation in these model (Fatima et al, 2008). Interestingly, FADD gene expression is down-regulated by NS-398 but upregulated by indomethacin in the colorectal cancer cell line Caco-2 (Huang et al, 2006).…”

“…Sulindac has been reported to down-regulate XRCC5, ERCC5 and UNG gene expression in colorectal cancer cell lines (Iizaka et al, 2002). Celecoxib up-regulated ATM, MAP3K2, CDKN1A and Bax gene expression in the colorectal cancer cell line HCA-7; in contrast, Bax gene expression was down-regulated in the HCT116 cell line upon celecoxib treatment (Fatima et al, 2008) suggesting that there may be variation in response from cell line to cell line to NSAID exposure. We have recently reported finding that XRCC3 protein expression in SW480 cells was increased upon 1 mM aspirin treatment for 48 hours (Dibra et al, 2010).…”

Apoptotic Effects of Etodolac in Breast Cancer Cell Cultures

“…Data indicated that there is an induction of pro-apoptotic response (Bax and Bid) in a dose-time-dependent manner. Global transcription proiling in colon cancers implied modulations on the genes related to cell cycle and apoptosis, but these changes were mostly observed in both COX-2 (+) and (-) cell lines [33]. Celecoxib induces cell cycle arrest at G1-phase, together with decreases in the inhibition of various cyclin expressions.…”

Celecoxib inhibits invasion and metastasis via a cyclooxygenase 2–independent mechanism in an in vitro model of Ewing sarcoma

“…We have shown that the cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) inhibits the development of pulmonary metastases without affecting growth of the primary tumor in a murine mode of ES [6,7]. The antitumor effects of COX-2 inhibitors, particularly celecoxib, have been the subject of intensive research in recent years [8][9][10][11], but the mechanism of celecoxib's antineoplastic effect has not been clearly elucidated.…”