Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas

Alexei Y. Savinov, Dmitri Rozanov, Vladislav S. Golubkov, F. Susan Wong, Alex Y. Strongin

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

We have discovered that clinically tested inhibitors of matrix metalloproteinases can control the functional activity of T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the onset of disease in a rodent model of type 1 diabetes in non-obese diabetic mice. We determined that MT1-MMP proteolysis of the T cell surface CD44 adhesion receptor affects the homing of T cells into the pancreas. We also determined that both the induction of the intrinsic T cell MT1-MMP activity and the shedding of cellular CD44 follow the adhesion of insulin-specific, CD8-positive, Kd-restricted T cells to the matrix. Conversely, inhibition of these events by AG3340 (a potent hydroxamate inhibitor that was widely used an clinical trials in cancer patents) impedes the transmigration of diabetogenic T cells into the pancreas and protects non-obese diabetic mice from diabetes onset. Overall, our studies have divulged a previously unknown function of MT1-MMP and identified a promising novel drug target in type I diabetes.

Original languageEnglish (US)
Pages (from-to)27755-27758
Number of pages4
JournalJournal of Biological Chemistry
Volume280
Issue number30
DOIs
StatePublished - Jul 29 2005
Externally publishedYes

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Matrix Metalloproteinase 14
T-cells
Pancreas
T-Lymphocytes
Medical problems
Pharmaceutical Preparations
Neoplasms
Inbred NOD Mouse
Type 1 Diabetes Mellitus
Proteolysis
Matrix Metalloproteinase Inhibitors
Patents
Cell membranes
Rodentia
Adhesion
Cell Membrane
Clinical Trials
Insulin

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas. / Savinov, Alexei Y.; Rozanov, Dmitri; Golubkov, Vladislav S.; Wong, F. Susan; Strongin, Alex Y.

In: Journal of Biological Chemistry, Vol. 280, No. 30, 29.07.2005, p. 27755-27758.

Research output: Contribution to journalArticle

Savinov, Alexei Y. ; Rozanov, Dmitri ; Golubkov, Vladislav S. ; Wong, F. Susan ; Strongin, Alex Y. / Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 30. pp. 27755-27758.
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