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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use
-
Cell Death / drug effects
-
Colonic Neoplasms / drug therapy*
-
Colonic Neoplasms / enzymology*
-
Colonic Neoplasms / genetics
-
Colonic Neoplasms / pathology
-
Drug Screening Assays, Antitumor
-
Epoxide Hydrolases / metabolism
-
GPI-Linked Proteins / metabolism
-
Gene Expression Regulation, Neoplastic / drug effects
-
HT29 Cells
-
Humans
-
Immunoassay
-
Leukotriene B4 / metabolism
-
Matrix Metalloproteinase 7 / genetics
-
Matrix Metalloproteinase 7 / metabolism*
-
Matrix Metalloproteinases, Membrane-Associated / metabolism
-
Mice
-
Proteomics
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Ribosomal Proteins / metabolism
-
Sulindac / analogs & derivatives*
-
Sulindac / pharmacology
-
Sulindac / therapeutic use
-
Trypsin / metabolism
Substances
-
Antineoplastic Agents
-
GPI-Linked Proteins
-
RNA, Messenger
-
RPL19 protein, human
-
Ribosomal Proteins
-
Sulindac
-
Leukotriene B4
-
sulindac sulfide
-
Epoxide Hydrolases
-
Trypsin
-
Matrix Metalloproteinases, Membrane-Associated
-
matrix metalloproteinase 25
-
Matrix Metalloproteinase 7
-
leukotriene A4 hydrolase