Fibroblast activation protein-α and dipeptidyl peptidase IV (CD26): Cell-surface proteases that activate cell signaling and are potential targets for cancer therapy

2005 ◽  
Vol 8 (1-2) ◽  
pp. 51-58 ◽  
Author(s):  
T KELLY
Keyword(s):  
Cancer Therapy ◽  
Cell Surface ◽  
Cell Signaling ◽  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Dipeptidyl Peptidase Iv ◽  
Fibroblast Activation ◽  
Activate Cell

scholarly journals Fibroblast activation protein: A cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis

Hepatology ◽  
1999 ◽  
Vol 29 (6) ◽  
pp. 1768-1778 ◽  
Author(s):  
Miriam T. Levy ◽  
Geoffrey W. McCaughan ◽  
Catherine A. Abbott ◽  
John E. Park ◽  
Anne M. Cunningham ◽  
...  
Keyword(s):  
Cell Surface ◽  
Protein A ◽  
Stellate Cells ◽  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Tissue Remodelling ◽  
Fibroblast Activation ◽  
A Cell

Inhibitors of Fibroblast Activation Protein (FAP) Inhibit Primary Myeloma Growth and Osteoclastogenesis Ex Vivo and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 813-813
Author(s):  
Angela Pennisi ◽  
Xin Li ◽  
Dana Gaddy ◽  
Nisreen Akel ◽  
Nazneen Aziz ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Surface ◽  
Cell Survival ◽  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Peptidase Activity ◽  
Dependent Manner ◽  
Pretreatment Level ◽  
Fibroblast Activation

Abstract Fibroblast activation protein (FAP), a cell surface serine protease with both dipeptidyl peptidase and collagenase activity, is selectively expressed by tumor stroma and involved in tumor metastasis. We have reported that FAP is upregulated in myelomatous bone and is overexpressed in osteoclasts after coculture with myeloma (MM) cells. FAP is not expressed by MM cells and FAP siRNA reduced MM cell survival in cocultures (Ge et al., BJH 2006). The aim of the study was to investigate the effect of FAP inhibitors, PT-100 and PT-630 on MM cell growth and osteoclastogenesis using coculture system and the SCID-hu model for primary MM. PT-630 inhibits cell surface dipeptidyl peptidase activity while PT-100 also inhibits intracellular activity of these enzymes. MM cells from 6 patients were cocultured with osteoclasts and treated twice a day with PT-100 and PT-630 (0.1–100 μM) for 5–7 days. Whereas PT-100 effectively inhibited MM cell growth in all tested doses by 38%–62% (p<0.002 vs. 100 μM), PT-630 inhibited MM cell growth in a dose dependent manner reaching 45% growth inhibition with 100 μM (p<0.02). These compounds had no direct effect on MM cell survival. Moreover, recombinant FAP had no impact on MM cells cultured alone, suggesting that FAP-induced MM cell survival depends on close contact between MM cells and osteoclasts. The anti-MM effect of PT-100 in cocultures was mediated through downregulation of phosphorylated p38 in MM cells as detected by Phospho MAPK array and confirmed by Western blot. MMP-2 and MMP-9 have been associated with FAP activity. The level of MMP-2 but not MMP-9 was reduced in coculture conditioned media by 44±7% (p<0.04) following treatment with PT-100 while PT-630 had no significant effect on production of these matrix metalloproteinases. To test effect on osteoclastogenesis, osteoclast precursors were incubated with RANKL and M-CSF in the absence and presence of PT-100 (1 μM) and PT-630 (10 μM) for 5–7 days. PT-100 and PT-630 inhibited formation of multinucleated osteoclasts by 78±6% (p<0.001) and 56±6% (p<0.003), respectively. Culture of osteoclasts on dentine slices in the presence of PT-100 and PT-630 reduced resorption pit area by 92% (p<0.01) and 69% (p<0.04), respectively. The anti-osteoclastogenic effects were mediated through inhibition of phosphorylated p38 MAPK in osteoclastic cultures in a dose related manner. In vivo, SCID-hu mice engrafted with MM cells from 4 patients were orally treated for 4–5 weeks with PT-100 (20 mg/day) and PT-630 (200 mg/day). These agents inhibited MM growth in 2 experiments, delayed growth in one experiment and had no effect on MM in an additional experiment. Overall, final hIg levels in hosts treated with vehicle, PT-100 and PT-630 were 355±170, 183±78 and 76±27 mg/ml, respectively. Bone mineral density (BMD) of the myelomatous bone was increased in responding hosts (3% vs. -32% change from pretreatment level in control) and had reduced severity of bone loss in myelomatous bone of nonresponding hosts (−15% vs. −28% change from pretreatment level in control), suggesting that, as shown in vitro, these agents directly affect bone cell function in vivo. We conclude that FAP is critically involved in MM osteolysis and tumor growth and thus approaches to inhibit FAP activity in myelomatous bone may help control MM and its associated bone disease.

scholarly journals A Role for Dipeptidyl Peptidase IV in Suppressing the Malignant Phenotype of Melanocytic Cells

1999 ◽  
Vol 190 (3) ◽  
pp. 311-322 ◽  
Author(s):  
Umadevi V. Wesley ◽  
Anthony P. Albino ◽  
Shakuntala Tiwari ◽  
Alan N. Houghton
Keyword(s):  
Growth Factors ◽  
Cell Surface ◽  
Serine Protease ◽  
Protease Activity ◽  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Dipeptidyl Peptidase Iv ◽  
Exogenous Growth ◽  
Serine Protease Activity ◽  
Exogenous Growth Factors

Dipeptidyl peptidase IV (DPPIV) is a cell surface peptidase expressed by normal melanocytes, epithelial cells, and other cells. Malignant cells, including melanomas and carcinomas, frequently lose or alter DPPIV cell surface expression. Loss of DPPIV expression occurs during melanoma progression at a stage where transformed melanocytes become independent of exogenous growth factors for survival. Tetracycline-inducible expression vectors were constructed to express DPPIV in human melanoma cells. Reexpressing DPPIV in melanoma cells at or below levels expressed by normal melanocytes induced a profound change in phenotype that was characteristic of normal melanocytes. DPPIV expression led to a loss of tumorigenicity, anchorage-independent growth, a reversal in a block in differentiation, and an acquired dependence on exogenous growth factors for cell survival. Suppression of tumorigenicity and reversal of a block in differentiation were dependent on serine protease activity, assessed using mutant DPPIV molecules containing serine→alanine substitutions. Surprisingly, dependence on exogenous growth factors was not dependent on serine protease activity. Reexpression of either wild-type or mutant DPPIV rescued expression of a second putative cell surface serine peptidase, fibroblast activation protein α, which can form a heterodimer with DPPIV. This observation suggests that rescue of fibroblast activation protein α may play a role in regulating growth of melanocytic cells. These results support the view that downregulation of DPPIV is an important early event in the pathogenesis of melanoma.

Coupled expression of dipeptidyl peptidase-IV and fibroblast activation protein-α in transformed astrocytic cells

2011 ◽  
Vol 354 (1-2) ◽  
pp. 283-289 ◽  
Author(s):  
Eva Balaziova ◽  
Petr Busek ◽  
Jarmila Stremenova ◽  
Lucie Sromova ◽  
Evzen Krepela ◽  
...  
Keyword(s):  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Dipeptidyl Peptidase Iv ◽  
Fibroblast Activation
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