Abstract
Matrix metalloproteinase 7 (MMP7), a metallohydrolase involved in the development of several cancers, is downregulated in the ApcMin/+ 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.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs), such as sulindac, are chemo-preventive reagents towards colorectal cancers [1,2,3]
It was reported that two days of sulindac treatment is sufficient to downregulate matrix metalloproteinase 7 (MMP7) in tumors of ApcMin/+ mice [7]
In order to determine if other matrix metalloproteases (MMPs), other classes of proteases, and the housekeeping gene, RPL-19, were affected by sulindac in HT-29 cells, reverse transcription–polymerase chain reaction (RT-PCR) and Western blot analyses were performed. mRNA for MMP25, trypsin1, and RPL-19 were not altered after sulindac sulfide treatment (Figure 3A, B)
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs), such as sulindac, are chemo-preventive reagents towards colorectal cancers [1,2,3] This effect is consistent with observations in vitro in human colon cancer cells [4], as well as in vivo in the ApcMin/+ mouse model, where a large decrease in tumor burden is observed [5]. MMP7 deletion in ApcMin/+ mice has been shown to strongly reduce intestinal tumor burden [9]. These observations implicate MMP7 as a viable target for the development of novel treatment regimes
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