Fibroblast activation protein-α in fibrogenic disorders and cancer: more than a prolyl-specific peptidase?

Abstract

Fibroblast activation protein-α (FAP-α) belongs to the family of prolyl-specific serine proteases. FAP-α displays both exopeptidase and endopeptidase/gelatinase/collagenase activities. FAP-α protein and/or activity have been associated with fibrosis, inflammation and cancer, but the protein is undetectable in most normal tissues. FAP-α is selectively expressed at sites of tissue remodeling and repair and enhances tumor progression, suggesting that this protease may be a therapeutic target to treat human disorders associated with fibrotic dysregulation. Areas covered: In this review, we summarize the mechanisms driving tissue fibrosis and describe some of the enzymes involved in fibrosis, concentrating on FAP-α. We describe its enzymatic properties, discuss the tools developed to control its activity and the problem of selectivity toward the other proteases of the family and outline its potential biological substrates. We also consider non-enzymatic functions of this protein and suggest that repression of FAP-α expression may represent therapeutic options. Expert opinion: Questions remain regarding the biological functions of FAP-α, either dependent or independent of its enzyme activity. However, as progress is underway to develop FAP-α-specific inhibitors and therapeutic antibodies, its role in diseases associated with fibrosis is starting to emerge, ultimately leading to novel therapeutic options for inflammatory and oncologic diseases.

Identification of Novel Natural Substrates of Fibroblast Activation Protein-alpha by Differential Degradomics and Proteomics

“…Inhibition of FAP increases the levels of active FGF-21 in obese mice more than in lean mice, demonstrating a metabolic benefit of FAP inhibition (15), which might be exploited for treating diabetes. Up-regulated expression of FAP is predominantly associated with disease states, including but not lim-ited to tumorigenesis, fibrotic conditions and atherosclerosis (5,6,16,17). Therefore, FAP is emerging as a promising marker of disease and much attention focuses upon exploiting this protease as a therapeutic target (4 -6, 18).…”

microRNA‐30a attenuates TGF‐β1–induced activation of pulmonary fibroblast cell by targeting FAP‐α

“…FAP is significantly up‐regulated in a variety of diseases including liver fibrosis, atherosclerosis and arthritis, and it has gradually become a unique therapeutic target of fibrosis . In pulmonary fibrosis, Fan et al found that FAP could participate in collagen catabolism and clearance and has a protective effect on pulmonary fibrosis .…”

Fibrogenic Disorders in Human Diseases: From Inflammation to Organ Dysfunction

“…75,[154][155][156] Others (Figure 14). Therapeutic attempts have also included targeting histone H4 acetylation, NDI-010976/ND630 (123) RO6842262 (124) GLPG1690 (125) BMS-986020/AM152 (126) roflumilast (127) pentoxifylline (128) sildenafil (129) PF-00489791 (130) inhibition of the Ca 2+ -activated K + channel (KCa3.1), the mineralocorticoid/aldosterone receptors or the vitamin D-dependent pathways. TGF-β1-or PDGF-mediated profibrotic and inflammatory responses in lung fibroblasts of patients with IPF were attenuated by the bromodomain 4 (Brd4)…”

“…discussing the outcomes of these trials. 5,6,42,63,82,124,135,136,163 The information obtained is summarized in Table 1. 51,137 Two very recent clinical reviews have analyzed clinical trials performed for IPF.…”

“…Specific inhibitors have been developed against the proteases able to process biologically active prolyl-containing peptides: DPP IV, FAP-α and POP/PREP 72,124. DPP IV/CD26 is a co-stimulator of T-cells and a therapeutic target for type-2 diabetes.…”