Biomedical Engineering Reference
In-Depth Information
The exact mechanisms of the extra-enzymatic roles of DPP-4 in cell biology,
cancer, and the immune system remain to be elucidated. Ongoing research
should be encouraged, as understanding such mechanisms could lead to future
targeting strategies involving activation or inhibition of ligand-binding sites.
With respect to the current use of DPP-4 inhibitors for metabolic disorders, it is
important to recognize that there is as yet no direct evidence that the extra-
enzymatic roles of DPP-4 are not influenced by enzyme inhibitors.
5.3 FAP
5.3.1 Functions of FAP
FAP is an important member of the DPP family of serine proteases. Containing a
similar structure and catalytic triad as DPP-4, FAP is also capable of cleaving the
post-proline bond. However, in addition to its dipeptidyl peptidase activity, 119,120
FAP also has endopeptidase activity. 121,122 The two known endopeptidase sub-
strates are denatured type I collagen 120,123 and a2-antiplasmin. 124,125 Given that
FAP expression is associated with wound healing, malignant tumor growth, and
chronic inflammation, which all involve extracellular matrix (ECM) degradation,
the gelatinase activity of FAP may contribute to these processes. 119,120,126
Similar to DPP-4, FAP has both extra-enzymatic and enzymatic functions.
Little is known about the extra-enzymatic capabilities of FAP, but it has been
shown to bind to urokinase plasminogen activator receptor (uPAR). 127,128
Another uPAR ligand, urokinase plasminogen activator, converts plasminogen
into its active form, plasmin, which degrades fibrin and other ECM compo-
nents. Therefore, the formation of the heterogeneous proteolytic complex
between FAP and uPAR might enhance the invasive and metastatic ability of
tumor cells. 127,128
FAP is upregulated in a number of epithelial cancers, and some studies
indicate that FAP may promote malignancy of certain tumors. Overexpression
of FAP in the LX2 hepatic stellate cell line enhances adhesion and migration on
collagen and fibronectin, 3 consistent with a role for FAP in liver fibrosis, which
is a cancer-prone environment. In vivo, FAP-expressing human breast cancer
cells, when xenografted into severe combined immunodeficient (SCID) mice,
lead to significantly greater tumorigenicity compared to control mice. 129
Similarly, FAP-overexpressing human embryonic kidney cells (HEK293T),
when xenografted into SCID mice, result in a significantly greater incidence of
tumor growth and development compared to cells expressing an enzyme
inactive variant of FAP. 130,131 Thus, the overall tumorigenic mechanism of
FAP may involve both extra-enzymatic and enzymatic functions. Thus, for
maximum therapeutic effect, it might be necessary to influence both functions.
However, other evidence points to the extra-enzymatic activity of FAP having
anti-tumorigenic effects, and retaining such effects would be an advantage
achieved when administering a FAP-selective enzyme inhibitor. Overexpression
of either wildtype FAP or FAP enzyme inactive mutants in the HEK293T
epithelial cell
line decreases cell adhesion on collagen I, fibronectin, and
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