Proteomic profiling identifies cyclooxygenase-2-independent global proteomic changes by celecoxib in colorectal cancer cells

Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 10/2006; 15(9):1598-606. DOI: 10.1158/1055-9965.EPI-06-0216
Source: PubMed


Celecoxib, a selective inhibitor of the enzyme cyclooxygenase-2 (COX-2), has been shown to be a promising chemoprevention agent. The chemopreventive efficacy of celecoxib is believed to be a consequence of its COX-2-dependent and COX-2-independent effects on a variety of cellular processes including proliferation, apoptosis, angiogenesis, and immunosurveillance. In an attempt to identify proteomic markers modulated by celecoxib that are independent of its inhibitory effect on COX-2, the colorectal cancer cell line HCT-116, a nonexpresser of COX-2, was treated with celecoxib. We used the powerful, state-of-the-art two-dimensional difference gel electrophoresis technology coupled with mass spectrometric sequencing to compare global proteomic profiles of HCT-116 cells before and after treatment with celecoxib. Among the differentially expressed proteins identified following celecoxib treatment were proteins involved in diverse cellular functions including glycolysis, protein biosynthesis, DNA synthesis, mRNA processing, protein folding, phosphorylation, redox regulation, and molecular chaperon activities. Our study presents a comprehensive analysis of large-scale celecoxib-modulated proteomic alterations, at least some of which may be mechanistically related to the COX-2-independent chemopreventive effect of celecoxib.

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    • "This result was further confirmed by GLI1 assay, suggesting that celecoxib may target HCT-116 cells via the SMO-independent modulation of GLI1 activity, as the HCT-116 cells were not sensitive to the SMO inhibitor, cyclopamine. A previous study also showed that celecoxib may widely regulate the expression of proteins in HCT-116 cells based on proteomic profiles, and degrade GLI1 by downregulating molecular chaperone activities, activating tumor suppressors and regulating the expression of peroxiredoxin I and creatine kinase, among others (25). In another study, a similar result showed that celecoxib induces the proteasome-dependent degradation of T-cell factor-1 and −4 in HCT-116 cells (26). "
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    ABSTRACT: Hedgehog (Hh) signaling is activated in numerous malignant tumors, but its role in human colorectal cancer remains uncertain. Celecoxib, a selective cyclooxygenase-2 inhibitor, has been shown to exhibit chemoprevention in colorectal cancer, however, the effects of celecoxib on Hh signaling remain unknown. The current study presents an evaluation of Hh signaling in colon cancer cell lines and the effects of celecoxib in vitro. Active Hh signaling was observed in LoVo and HT-29 cells, with particularly high levels in the LoVo cells. However, Hh signaling activity was absent in HCT-116 cells. Quantitative polymerase chain reaction indicated that the expression of Hh receptor patched homolog 1 (PTCH1) was absent in the LoVo cells, but that they exhibited high levels of glioma-associated oncogene homolog-1 (GLI1) expression, while high expression levels of PTCH1 and low expression levels of smoothened (SMO) and GLI1 were observed in the HCT-116 cells. The HCT-116 cells were extremely sensitive to celecoxib, whereas the LoVo cells were resistant to the anticancer effect of the drug. Celecoxib downregulated the expression of GLI1 in the HCT-116 and HT-29 cells, but did not change the expression of GLI1 in the LoVo cells. The results presented in this study indicated that the anticancer effect of celecoxib is selective in colon cancer cells; celecoxib may target cancer cells via the SMO-independent modulation of GLI1 activity, and Hh signaling may be significant in maintaining the malignant state of LoVo cells. These findings may aid in improving our understanding of the carcinogenesis of colon cancer and the development of novel approaches for the targeted therapy of this disease.
    Oncology letters 11/2014; 8(5):2203-2208. DOI:10.3892/ol.2014.2439 · 1.55 Impact Factor
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    • "For example, celecoxib (Celebrex®; Pfizer, Inc, New York, NY, USA), originally a widely prescribed nonsteroidal anti-inflammatory drug, has recently been shown to have anticancer properties95,96 with uncertain mechanisms, ranging from modulating the expression of Bcl-2 family members and mitochondria-mediated apoptosis,95,97 to inhibiting nuclear factor kappa B,98,99 Akt,100 and Stat3101signaling pathways. Proteomic analysis of human oral squamous cell carcinoma found that celecoxib treatment induced ten- to 20-fold overexpression of heterogeneous nuclear ribonuclear protein C.102 Similarly, global proteomic profiles of colorectal cancer cells before and after treatment with celecoxib revealed significant alterations among multiple proteins involved in diverse cellular functions ranging from glycolysis, protein biosynthesis, DNA synthesis, messenger RNA processing, protein folding, phosphorylation, redox regulation, to molecular chaperon activities.103 However, none of the proteomic studies has been conclusive in the mechanistic interpretation of numerous alterations in protein expression. "
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    ABSTRACT: Proteomic approaches are continuing to make headways in cancer research by helping to elucidate complex signaling networks that underlie tumorigenesis and disease progression. This review describes recent advances made in the proteomic discovery of drug targets for therapeutic development. A variety of technical and methodological advances are overviewed with a critical assessment of challenges and potentials. A number of potential drug targets, such as baculoviral inhibitor of apoptosis protein repeat-containing protein 6, macrophage inhibitory cytokine 1, phosphoglycerate mutase 1, prohibitin 1, fascin, and pyruvate kinase isozyme 2 were identified in the proteomic analysis of drug-resistant cancer cells, drug action, and differential disease state tissues. Future directions for proteomics-based target identification and validation to be more translation efficient are also discussed.
    Drug Design, Development and Therapy 10/2013; 7:1259-1271. DOI:10.2147/DDDT.S52216 · 3.03 Impact Factor
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    • "Celecoxib is a paradigmatic selective inhibitor of COX-2. This anti-inflammatory drug has potent anti-tumor activity in a wide variety of human tumor types, such as colorectal, breast, and lung cancers [8-10]. "
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    ABSTRACT: Background Cyclooxygenase-2(COX-2) promotes carcinogenesis, tumor proliferation, angiogenesis, prevention of apoptosis, and immunosuppression. Meanwhile, COX-2 over-expression has been associated with tumor behavior and prognosis in several cancers. This study investigated the antitumor effects of the selective COX-2 inhibitor, Celecoxib, on breast cancer in vitro and in vivo. Methods Human breast cancer MCF-7 and MDA-MB-231 cells were cultured with different concentration (10, 20, 40 μmol/L) of celecoxib after 0-96 hours in vitro. MTT assay was used to determine the growth inhibition of breast cancer cells in vitro. The expression of COX-2 on mRNA was measured by real-time quantitive PCR analysis. Flow cytometry was performed to analyze the cell cycle of MCF-7 cells. Levels of PGE2 were measured by ELISA method. The in vivo therapeutic effects of celecoxib were determined using rat breast cancer chemically induced by 7,12-dimethylben anthracene (DMBA). Results The inhibition of proliferation of both MCF-7 and MDA-MB-231 cells in vitro by celecoxib was observerd in time and dose dependent manner. Celecoxib effectively down-regulated the expression of COX-2. The cell cycle was arrested at G0/G1, and rate of cells in S phase was obviously decreased. Levels of PGE2 were inhibited by Celecoxib. The tumor incidence rate of the celecoxib group was lower than that of the control group. In addition, the tumor latency period of the celecoxib group was longer than that of the control group. Conclusions Celecoxib inhibited the proliferation of breast cancer cell lines in vitro, and prevented the occurrence of rat breast cancer chemically induced by DMBA. Therefore, celecoxib exhibits an antitumor activity and seems to be effective in anti-tumor therapy.
    Cancer Cell International 12/2012; 12(1):53. DOI:10.1186/1475-2867-12-53 · 2.77 Impact Factor
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