The Role of Post-Translational Modifications of Chemokines by CD26 in Cancer

Abstract

Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer. Both tumor-promoting and -impeding roles have been ascribed to chemokines, which they exert in a direct or indirect manner. An important post-translational modification that regulates chemokine activity is the NH2-terminal truncation by peptidases. CD26 is a dipeptidyl peptidase (DPPIV), which typically clips a NH2-terminal dipeptide from the chemokine. With a certain degree of selectivity in terms of chemokine substrate, CD26 only recognizes chemokines with a penultimate proline or alanine. Chemokines can be protected against CD26 recognition by specific amino acid residues within the chemokine structure, by oligomerization or by binding to cellular glycosaminoglycans (GAGs). Upon truncation, the binding affinity for receptors and GAGs is altered, which influences chemokine function. The consequences of CD26-mediated clipping vary, as unchanged, enhanced, and reduced activities are reported. In tumors, CD26 most likely has the most profound effect on CXCL12 and the interferon (IFN)-inducible CXCR3 ligands, which are converted into receptor antagonists upon truncation. Depending on the tumor type, expression of CD26 is upregulated or downregulated and often results in the preferential generation of the chemokine isoform most favorable for tumor progression. Considering the tight relationship between chemokine sequence and chemokine binding specificity, molecules with the appropriate characteristics can be chemically engineered to provide innovative therapeutic strategies in a cancer setting.

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

“…Through their enzymatic activities, DPP4, FAP, APN, and ADAM17 mediate the proteolysis of bioactive peptides and cytokines, components of the extracellular matrix, and transmembrane proteins (receptors and adhesion molecules) [8,[10][11][12][13][15][16][17][18][19][20][21][22]. Ectoprotease interaction with their inhibitors or specific monoclonal antibodies (mAbs) has revealed that these ectoenzymes regulate intracellular key signalling pathways related to the modulation of major cell events (proliferation, survival, migration, angiogenesis) [11][12][13]18,20,[22][23][24][25][26][27][28][29] (Figure 1). The enzymatic activity of DPP4, FAP, APN, and ADAM17, even if it contributes, is not essential for signal transduction.…”

Evaluation of Blood Soluble CD26 as a Complementary Biomarker for Colorectal Cancer Screening Programs

“…However, our work can be related to the new studies using screening settings from individuals with adenomas and polyps or using panels of inflammatory biomarkers [ 11 , 14 , 15 ]. In fact, most data relate the changes of sCD26 levels with the immune system [ 18 , 24 , 25 , 26 , 40 , 41 ] with probable impact, as deduced from pre-clinical models, in DPP4 substrates such as certain chemokines [ 42 , 43 ]. This biomarker, therefore, is in line with a recently implemented Systemic Immune-Inflammation Index for CRC [ 44 ].…”

Near-Infrared Photoimmunotherapy for Thoracic Cancers: A Translational Perspective

“…CD26 is a type II transmembrane protein that recognizes chemokines with the penultimate proline or alanine and cleaves the NH2-terminal dipeptide [ 83 , 84 ]. Immunohistochemical analysis has shown that CD26 is highly expressed in MPM cells, indicating its pro-carcinogenic function and relevance as a prognostic marker [ 85 ].…”