Dipeptidyl peptidase IV (DPPIV) is a multifunctional
cell-surface protein that, as well as having
dipeptidase activity, is the major
binding protein for
adenosine deaminase (ADA) and also binds
extracellular matrix proteins such as
fibronectin and
collagen. It typically reduces the activity of
chemokines and other
peptide mediators as a result of its enzymatic activity. DPPIV is aberrantly expressed in many
cancers, and decreased expression has been linked to increases in invasion and
metastasis. We asked whether
adenosine, a
purine nucleoside that is present at increased levels in the hypoxic tumor microenvironment, might affect the expression of DPPIV at the cell surface. Treatment with a single dose of
adenosine produced an initial transient (1 to 4 hours) modest (approximately 10%) increase in DPPIV, followed by a more profound (approximately 40%) depression of DPPIV
protein expression at the surface of HT-29 human colon
carcinoma cells, with a maximal decline being reached after 48 hours, and persisting for at least a week with daily exposure to
adenosine. This down-regulation ofDPPIV occurred at
adenosine concentrations comparable to those present within the extracellular fluid of
colorectal tumors growing in vivo, and was not elicited by
inosine or
guanosine. Neither cellular uptake of
adenosine nor its phosphorylation was necessary for the down-regulation of DPPIV. The decrease in DPPIV
protein at the cell surface was paralleled by decreases in DPPIV
enzyme activity, binding of ADA, and the ability of the cells to bind to and migrate on cellular
fibronectin.
Adenosine, at concentrations that exist within solid
tumors, therefore acts at the surface of
colorectal carcinoma cells to decrease levels and activities of DPPIV. This down-regulation of DPPIV may increase the sensitivity of
cancer cells to the
tumor-promoting effects of
adenosine and their response to
chemokines and the extracellular matrix, facilitating their expansion and
metastasis.