Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway.

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 mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation, and decreases levels of urokinase-type 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.

[1]  A. Houghton,et al.  Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells , 2004, International journal of cancer.

[2]  A. Mazar,et al.  Enhanced invasion of hormone refractory prostate cancer cells through hepatocyte growth factor (HGF) induction of urokinase‐type plasminogen activator (u‐PA) , 2004, The Prostate.

[3]  L. Kelley,et al.  Increased levels of urokinase plasminogen activator receptor in prostate cancer cells derived from repeated metastasis , 2004, World Journal of Urology.

[4]  Leif E. Peterson,et al.  Fibroblast growth factor 2 promotes tumor progression in an autochthonous mouse model of prostate cancer. , 2003, Cancer research.

[5]  C. V. van Noorden,et al.  The multifunctional or moonlighting protein CD26/DPPIV. , 2003, European journal of cell biology.

[6]  H. Nawashiro,et al.  Nuclear Accumulation of Basic Fibroblast Growth Factor as a Predictor for the Recurrence of Pituitary Adenomas , 2002, Journal of Neuro-Oncology.

[7]  A. Galloway,et al.  Lack of ERK activation and cell migration in FGF‐2‐deficient endothelial cells , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  M. Ittmann,et al.  Role of fibroblast growth factor receptor signaling in prostate cancer cell survival. , 2001, Journal of the National Cancer Institute.

[9]  D. Feldman,et al.  The development of androgen-independent prostate cancer , 2001, Nature Reviews Cancer.

[10]  A. Mazar,et al.  The role of the plasminogen activation system in angiogenesis and metastasis. , 2001, Surgical oncology clinics of North America.

[11]  P. Kantoff,et al.  Vascular endothelial growth factor and basic fibroblast growth factor urine levels as predictors of outcome in hormone-refractory prostate cancer patients: a cancer and leukemia group B study. , 2001, Cancer research.

[12]  M. Korc,et al.  Expression of the High Molecular Weight Fibroblast Growth Factor-2 Isoform of 210 Amino Acids Is Associated with Modulation of Protein Kinases C δ and ε and ERK Activation* , 2001, The Journal of Biological Chemistry.

[13]  J. Schwarzbauer,et al.  Regulation of fibronectin matrix assembly by activated Ras in transformed cells , 2000, Oncogene.

[14]  R. deVere White,et al.  Fibroblast growth factor 2: its structure and property, paracrine function, tumor angiogenesis, and prostate-related mitogenic and oncogenic functions. , 2000, Urology.

[15]  I. Delrieu.  The high molecular weight isoforms of basic fibroblast growth factor (FGF‐2): an insight into an intracrine mechanism , 2000, FEBS letters.

[16]  J. Jouanneau,et al.  Nuclear 24 kD fibroblast growth factor (FGF)-2 confers metastatic properties on rat bladder carcinoma cells , 1999, Oncogene.

[17]  L. Luttrell,et al.  Activation of extracellular signal-regulated kinase in human prostate cancer. , 1999, The Journal of urology.

[18]  A. Houghton,et al.  A Role for Dipeptidyl Peptidase IV in Suppressing the Malignant Phenotype of Melanocytic Cells , 1999, The Journal of experimental medicine.

[19]  M. Presta,et al.  Role of endothelial cell extracellular signal-regulated kinase1/2 in urokinase-type plasminogen activator upregulation and in vitro angiogenesis by fibroblast growth factor-2. , 1999, Journal of cell science.

[20]  Xiaoen Wang,et al.  High‐malignancy orthotopic nude mouse model of human prostate cancer LNCaP , 1999, The Prostate.

[21]  M. Ittmann,et al.  Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  S. Shankland,et al.  Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1). , 1999, The Journal of clinical investigation.

[23]  P. Allavena,et al.  Truncation of Macrophage-derived Chemokine by CD26/ Dipeptidyl-Peptidase IV beyond Its Predicted Cleavage Site Affects Chemotactic Activity and CC Chemokine Receptor 4 Interaction* , 1999, The Journal of Biological Chemistry.

[24]  H. Frierson,et al.  Activation of mitogen-activated protein kinase associated with prostate cancer progression. , 1999, Cancer research.

[25]  V. Reuter,et al.  Expression and localization of aminopeptidase A, aminopeptidase N, and dipeptidyl peptidase IV in benign and malignant human prostate tissue , 1997, The Prostate.

[26]  H. Klocker,et al.  Basic fibroblast growth factor levels in cancer cells and in sera of patients suffering from proliferative disorders of the prostate , 1997, The Prostate.

[27]  F. Schröder,et al.  Orthotopic implantation of human prostate cancer cell lines: A clinically relevant animal model for metastatic prostate cancer , 1997, The Prostate.

[28]  M. Nangaku,et al.  Mesangial cell proliferation mediated by PDGF and bFGF is determined by levels of the cyclin kinase inhibitor p27Kip1. , 1997, Kidney international.

[29]  D. Rifkin,et al.  Biological roles of fibroblast growth factor-2. , 1997, Endocrine reviews.

[30]  K. Sekiguchi,et al.  Suppression of transformed phenotypes of human fibrosarcoma cells by overexpression of recombinant fibronectin. , 1996, Cancer research.

[31]  Y. Miller,et al.  Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux. , 1996, Cancer research.

[32]  M. Brawer,et al.  Serum basic fibroblast growth factor in men with and without prostate carcinoma , 1995, Cancer.

[33]  M. Shipp,et al.  CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation. , 1994, The Journal of clinical investigation.

[34]  M. Gleave,et al.  Derivation of androgen‐independent human LNCaP prostatic cancer cell sublines: Role of bone stromal cells , 1994, International journal of cancer.

[35]  J. Sakamoto,et al.  Distribution of adenosine deaminase binding protein in normal and malignant tissues of the gastrointestinal tract studied by monoclonal antibodies , 1993, Journal of surgical oncology.

[36]  G. Chodak,et al.  Basic fibroblast growth factor in human prostate cancer cells. , 1992, Cancer research.

[37]  H. Prats,et al.  Alternative initiation of translation determines cytoplasmic or nuclear localization of basic fibroblast growth factor , 1991, Molecular and cellular biology.

[38]  H. Tanke,et al.  Adenosine deaminase complexing protein (ADCP) expression and metastatic potential in prostatic adenocarcinomas , 1990, The Journal of pathology.

[39]  G. Piazza,et al.  Evidence for a role of dipeptidyl peptidase IV in fibronectin-mediated interactions of hepatocytes with extracellular matrix. , 1989, The Biochemical journal.

[40]  B. Binder,et al.  Urokinase-type plasminogen activator as a marker for the formation of distant metastases in prostatic carcinomas. , 1988, The Journal of urology.

[41]  B. Bauvois,et al.  A collagen-binding glycoprotein on the surface of mouse fibroblasts is identified as dipeptidyl peptidase IV. , 1988, The Biochemical journal.

[42]  C. Cordon-Cardo,et al.  Cell surface antigens of human melanocytes and melanoma. Expression of adenosine deaminase binding protein is extinguished with melanocyte transformation , 1988, The Journal of experimental medicine.

[43]  G. Murphy,et al.  LNCaP model of human prostatic carcinoma. , 1983, Cancer research.

[44]  D. Paulson,et al.  Isolation of a human prostate carcinoma cell line (DU 145) , 1978, International journal of cancer.

[45]  M. Georgescu,et al.  Synergy in tumor suppression by direct interaction of neutral endopeptidase with PTEN. , 2004, Cancer cell.

[46]  W. Isaacs,et al.  Androgen receptor outwits prostate cancer drugs , 2004, Nature Medicine.

[47]  J. Ware.  Growth Factor Network Disruption in Prostate Cancer Progression , 2004, Cancer and Metastasis Reviews.

[48]  M. Korc,et al.  Expression of the high molecular weight fibroblast growth factor-2 isoform of 210 amino acids is associated with modulation of protein kinases C delta and epsilon and ERK activation. , 2001, The Journal of biological chemistry.

[49]  M. Webber,et al.  Immortalized and tumorigenic adult human prostatic epithelial cell lines: Characteristics and applications part 2. Tumorigenic cell lines , 1997, The Prostate.

[50]  C. Abbott,et al.  Molecular analyses of human and rat dipeptidyl peptidase IV. , 1997, Advances in experimental medicine and biology.

[51]  A. Sedo,et al.  Dipeptidyl peptidase IV in cell proliferation and differentiation. , 1994, Sbornik lekarsky.

[52]  M. Shipp,et al.  Relationship to Cellular Proliferation , 1994 .