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      Effect of Sulindac Sulfide on Metallohydrolases in the Human Colon Cancer Cell Line HT-29

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          Abstract

          Matrix metalloproteinase 7 (MMP7), a metallohydrolase involved in the development of several cancers, is downregulated in the Apc Min/+ colon cancer mouse model following sulindac treatment. To determine whether this effect is relevant to the human condition, HT-29 human colon cancer cells were treated with sulindac and its metabolites, and compared to results obtained from in vivo mouse studies. The expression of MMP7 was monitored. The results demonstrated that sulindac sulfide effectively downregulated both MMP7 expression and activity. Furthermore, activity-based proteomics demonstrated that sulindac sulfide dramatically decreased the activity of leukotriene A4 hydrolase in HT-29 cells as reflected by a decrease in the level of its product, leukotriene B4. This study demonstrates that the effect of sulindac treatment in a mouse model of colon cancer may be relevant to the human counterpart and highlights the effect of sulindac treatment on metallohydrolases.

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          Most cited references22

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          Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.

          M M Wolfe, D R Lichtenstein, G. Singh (1999)
          Article 0 comments Cited 275 times – based on 0 reviews     Review now
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            Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin.

            K. Heppner, Lynn Matrisian, Alexandra B. Hogan … (1997)
            Matrix metalloproteinases (MMPs) classically have been implicated in basement membrane destruction associated with late-stage tumor cell invasion and metastasis. However, recent studies have demonstrated that one MMP family member, matrilysin, is expressed in a high percentage of early-stage human colorectal tumors. We analyzed matrilysin expression in benign intestinal tumors from mice heterozygous for the ApcMin allele (Min/+) and found that the mRNA was induced in the majority (88%) of these adenomas. Protein was detected in the tumor cells, where, surprisingly, it was predominantly immunolocalized to the lumenal surface of dysplastic glands rather than the basement membrane or extracellular matrix. To address the role of matrilysin in Min intestinal tumorigenesis, we generated Min/+ mice deficient in this MMP by gene targeting and homologous recombination. The absence of matrilysin resulted in a reduction in mean tumor multiplicity in Min/+ animals of approximately 60% and a significant decrease in the average tumor diameter. Based on these findings, we conclude that matrilysin is a suppressor of the Min phenotype, possibly by functioning in a capacity independent of matrix degradation. These results argue for the use of MMP inhibitors in the treatment and prevention of early-stage colon cancer.
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              Aminopeptidase N is involved in cell motility and angiogenesis: its clinical significance in human colon cancer.

              Masayuki Miyake, A Takabayashi, Hiroki Hashida … (2002)
              The molecular basis of cell motility is highly complex and is controlled by a number of molecular systems, whereas angiogenesis is an important biological component of tumor progression. The aims of this study were to investigate the possible involvement of proteins at the cell surface in controlling cell motility and angiogenesis, and to identify the cell surface molecules involved in gastrointestinal tumors. We addressed these issues using functional monoclonal antibodies, which inhibit cell motility, endothelial cell migration, and tube formation. Furthermore, we investigated the relationship between this antigen and colon cancer, and showed the prognostic significance in human colon cancer. We established a murine monoclonal antibody MH8-11, which inhibits cell motility and in vitro angiogenesis. This epitope was a 165-kilodalton protein, and the sequencing analysis revealed that it was almost identical to aminopeptidase N (APN)/cluster of differentiation (CD) 13. APN/CD13 expression was associated with tumor status (P = 0.025). The disease-free and overall survival rate for patients with positive APN/CD13 expression tumors was significantly lower than that for patients with negative APN/CD13 expression tumors (P = 0.014, 0.033, respectively). Among 47 node-positive patients, the survival rate of patients with negative APN/CD13 expression was better than that of those with positive APN/CD13 expression. Our data suggest that APN/CD13 is involved in cell motility and angiogenesis, and APN/CD13 expression may be a useful indicator of a poor prognosis for node-positive patients with colon cancer.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 3 October 2011
                Volume: 6
                Issue: 10
                Electronic Location Identifier: e25725
                Affiliations
                [1 ]W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America
                [2 ]Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America
                [3 ]Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, United States of America
                Stanford University, United States of America
                Author notes

                Conceived and designed the experiments: VAP FJC JT HGA. Performed the experiments: HGA JT. Analyzed the data: VAP FJC JT HGA. Contributed reagents/materials/analysis tools: HGA. Wrote the paper: VAP FJC JT HGA.

                Article
                Publisher ID: PONE-D-11-02554
                DOI: 10.1371/journal.pone.0025725
                PMC ID: 3185020
                PubMed ID: 21991341
                SO-VID: e7e21477-67bf-4ddc-8941-682a1a477143
                Copyright © Guillen-Ahlers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 3 February 2011
                Date accepted : 9 September 2011
                Page count
                Pages: 6
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Biochemistry
                Subject: Drug Discovery
                Subject: Biotechnology
                Subject: Drug Discovery
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Medicine
                Subject: Drugs and Devices
                Subject: Drug Research and Development
                Subject: Drug Discovery
                Subject: Gastroenterology and Hepatology
                Subject: Colon
                Subject: Gastrointestinal Cancers
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Gastrointestinal Tumors
                Subject: Colon Adenocarcinoma
                Subject: Basic Cancer Research
                Subject: Cancer Treatment

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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