Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

Abstract

Dipeptidyl peptidase IV (DPPIV) is a serine protease with tumor suppressor function. It regulates the activities of mitogenic peptides implied in cancer development. Progression of benign prostate cancer to malignant metastasis is linked to increased production of basic fibroblast growth factor (bFGF), a powerful mitogen. In this study, using in vitro model system we show that DPPIV loss is associated with increased bFGF production in metastatic prostate cancer cells. DPPIV reexpression in prostate cancer cells blocks nuclear localization of bFGF, reduces bFGF levels, inhibits mitogenactivated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation, and decreases levels of urokinasetype plasminogen activator, known downstream effectors of bFGF signaling pathway. These molecular changes were accompanied by induction of apoptosis, cell cycle arrest, inhibition of in vitro cell migration, and invasion. Silencing of DPPIV by small interfering RNA resulted in increased bFGF levels and restoration of mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation. These results indicate that DPPIV inhibits the malignant phenotype of prostate cancer cells by blocking bFGF signaling pathway. (Cancer Res 2005; 65(4): 1325-34)

Extracellular matrix degrading enzymes at the prostasome surface

“…Progression of benign prostate cancer to malignant metastasis is linked to increased production of basic fibroblast growth factor (bFGF), a powerful mitogen whose signaling pathway can be blocked by DPPIV thus inhibiting the malignant phenotype of prostate cancer cells. 28 Our results show a remarkable reduction of DPPIV activity, more marked in PC3. These findings are in agreement with the tumor-suppressing function of this enzyme.…”

Neutral endopeptidase inhibits prostate cancer tumorigenesis by reducing FGF-2-mediated angiogenesis

“…Of note, DPPIV-positive LNCaP cells showed low FGF-2 expression, while inhibition of DPPIV expression resulted in increased FGF-2 expression. 35 While these data support NEP inhibits prostate cancer tumorigenesis A Horiguchi et al the concept that membrane-associated peptidases such as NEP and DPPIV play an important role in the modulation of FGF-2 production by prostate cancer cells, it is unknown whether DPPIV and NEP coordinately regulate FGF-2 levels. FGF-2 has been studied extensively in prostate cancer.…”

“…[33][34][35] Recently, Wesley et al 35 reported an inverse relationship between DPPIV and FGF-2 expression in prostate cancer cells. DPPIV-negative DU145 cells showed high FGF-2 expression, while restoration of DPPIV expression resulted in markedly decreased FGF-2 expression, 35 which was similar to our results. Of note, DPPIV-positive LNCaP cells showed low FGF-2 expression, while inhibition of DPPIV expression resulted in increased FGF-2 expression.…”

Possible new therapeutic agents for malignant pleural mesothelioma: anti-CD26 monoclonal antibody and naftopidil

“…The active antimesothelioma agent PEM rapidly induces CD26 expression on the cell surface and inhibits in vivo tumor growth synergistically with YS110 [14]. The mechanisms of YS110 antitumor action for CD26-positive mesotheliomas are the following: (a) cell lysis of MPM cells via antibody-dependent cell-mediated cytotoxicity in addition to its direct antitumor effect via cyclin-dependent kinase (CDK) inhibitor p27 kip1 upregulation and disruption of binding to ECM [13]; (b) G1/S cell cycle arrest and G2/M cell cycle delay by upregulating CDK inhibitor p27 kip1 and p21 cip/ waf1 via multiple signaling pathways [13][14][15]; and (c) induction of nuclear translocation of cell-surface CD26 molecules by internalization of the CD26-YS110 complexes to inhibit proliferation of MPM cells via suppression of POLR2A gene expression [16]. The reduction of distant metastases by YS110 treatment in experimental models may be explained by CD26's function as a binding protein to distinct ECM proteins [13].…”