Neutral endopeptidase inhibits prostate cancer cell migration by blocking focal adhesion kinase signaling

Sumitomo, Makoto; Shen, Ruoqian; Walburg, Marc; Dai, Jie; Geng, Yiping; Navarro, Daniel; Boileau, Guy; Papandreou, Christos N.; Giancotti, Filippo G.; Knudsen, Beatrice S.; Nanus, David M.

doi:10.1172/jci10536

Cited by 137 publications

(144 citation statements)

References 45 publications

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“…Other studies performed in androgen-independent and -dependent PC cell models in vitro, demonstrated regulation, by androgens, of several other genes involved in modulating invasion ability of these cells, including prostin-1, 31 urokinasetype palsminogen activator 32 and neutral endopeptidase (NEP). 5 Here we show that EGF-mediated autotransphosphorylation of EGFR and downstream PI3K/AKT pathway activation are also reduced in androgen-sensitive cell lines. In addition, we demonstrate the occurrence of an interaction between the AR and the EGFR at the membrane level in the same cell lines.…”

Section: Egfr Internalization Is Altered In Pc3-ar Cellsmentioning

confidence: 59%

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

Bonaccorsi

Carloni

Muratori

et al. 2004

Intl Journal of Cancer

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We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of ␣6␤4 integrin expression. The treatment with androgens further reduced invasion of the cells without modifying ␣6␤4 expression, suggesting an interference with the invasion process by androgens. Here, we investigated EGF-mediated signal transduction processes that lead to invasion in PC3-AR cells. We show that EGF-induced EGFR autotransphosphorylation is reduced in PC3-AR cells compared to PC3 cells transfected only with the vector (PC3-Neo). EGF-stimulated PI3K activity, a key signaling pathway for invasion of these cells, and EGF-PI3K interaction are also decreased in PC3 Key words: prostate cancer; epidermal growth factor receptor; androgen receptor; PI3K; invasionProstate Cancer (PC) is one of the most common cancer and the second leading cause of death in American men. 1 Since prostate cancer cell growth is enhanced by androgens, in the advanced stages of the disease, androgen ablation therapy represents a valuable tool for the treatment of these patients. However the development in most patients after few years of treatment of androgenindependent clones, characterized by higher invasiveness and metastatic properties, has focused attention on the molecular mechanisms that lead to loss of androgen-dependence as well as on the pathways that are regulated by androgens in these cells besides proliferation. Indeed, although androgens are the major stimulus for proliferation of prostate cancer cells, maintenance of androgensensitivity appears to keep a more differentiated and less malignant phenotype of these cells. The ability to produce tumors in nude mice, for instance, is higher in androgen-insensitive cell lines (such as PC3 and DU145) with respect to androgen sensitive (LNCaP). 2 In this light, the role of androgens in the regulation of the pathways involved in invasion and metastasis represents a major task in studies on prostate cancer biology. 3 As a result, some androgen-regulated genes involved in signaling pathways that lead to invasion have been recently identified 4 -6 and their role in decreasing invasion ability of androgen-sensitive prostate cancer cells indicated. Migration and invasion of cancer cells is regulated by multiple pathways that employ various growth factor and their receptors, integrins and cytoskeletal elements. A key role is played by the EGF receptor (EGFR), which, following interaction with the integrin ␣6␤4, promotes cell migration through activation of PI3K and other downstream pathways. 7,8 In a previous study, we demonstrated that the expression of androgen receptor in PC3 cells by transfection with a full-length human androgen receptor expression vector (PC3-AR) determined a decrease in the expression of the integrin ␣6␤4 and in the ability of these cells to invade Matrigel in response to EGF. 6 The treatment with the synthetic androgen R1881 determined a ...

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Section: Egfr Internalization Is Altered In Pc3-ar Cellsmentioning

confidence: 59%

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

Bonaccorsi

Carloni

Muratori

et al. 2004

Intl Journal of Cancer

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“…Expression of wild-type NEP can also inhibit peptide-mediated FAK phosphorylation in TSU-Pr1 cells. 27 As shown in Figure 2d, expression of NEP in DU-NEP cells did not alter FAK phosphorylation in DU145 cells. Finally, the NEP protein physically associates with and stabilizes the PTEN tumor suppressor protein via a direct protein-protein interaction between the NEP cytoplasmic domain and a negatively charged phosphorylation site in PTEN C terminus.…”

Section: Lentiviral Nep Expression Effects On Du145 Cellsmentioning

confidence: 65%

“…Expression of NEP in TSU-Pr1 cells resulted in significant inhibition of cell growth and cell invasion. 4,7,11,27 In contrast, cell proliferation or cell invasion in DU-NEP cells was no different than DU-NEPmu or control DU-GFP cells (Figure 2a, b). NEP has been shown to inhibit Akt phosphorylation.…”

Section: Lentiviral Nep Expression Effects On Du145 Cellsmentioning

confidence: 88%

“…26,27 For immunoprecipitations, 600 mg of precleared total cell lysates were incubated with 2 mg of anti-PTEN antibody for 2 h at 41C and 40 ml of protein G-Sepharose beads (Amersham Pharmacia Biotech, Piscataway, NJ, USA) for 1 h. Protein complexes were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and detected with the appropriate antibody.…”

Section: Immunoblotting and Immunoprecipitationmentioning

confidence: 99%

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

Horiguchi

Chen

Goodman

et al. 2007

Prostate Cancer Prostatic Dis

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Neutral endopeptidase (NEP) is a cell surface peptidase that catalytically inactivates a variety of physiologically active peptides including basic fibroblast growth factor (FGF-2). We investigated the effect of using lentivirus to overexpress NEP in NEP-deficient DU145 prostate cancer cells. Third-generation lentiviral vectors encoding wild-type NEP (L-NEP), catalytically inactive mutant NEP (L-NEPmu), and green fluorescent protein (L-GFP) were stably introduced into DU145 cells. FGF-2 levels in cell culture supernatants decreased by 80% in L-NEP-infected DU145 cells compared to cells infected with L-NEPmu or L-GFP (Po0.05) while levels of other angiogenic factors were not altered. In vitro tubulogenesis of human vascular endothelial cells induced by conditioned media from DU145 cells infected with L-NEP was significantly reduced compared with that from DU145 cells infected with L-GFP (Po0.05). Tumor xenografts from L-NEP-infected DU145 cells were significantly smaller compared to control cell xenografts and vascularity within these tumors was decreased (Po0.05). Our data suggest that stable expression of NEP in DU145 cells inhibits prostate cancer tumorigenicity by inhibiting angiogenesis, with a probable mechanism being proteolytic inactivation of FGF-2.

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“…A major effect of ET A R activation is induction of the ILK pathway, leading to Snail1 and β-catenin nuclear localization and activation [112]. Phosphorylation of FAK and activation of the MAPK and PI3K/Akt transduction cascades are also mediated by ET-1/ET A R binding [113,114]. Increased expression of β1 integrins and disrupted gap junction communication has been linked to ET-1 as well [115,116].…”

Section: Et-1mentioning

confidence: 99%

Toward an Integrative Analysis of the Tumor Microenvironment in Ovarian Epithelial Carcinoma

Serio

2011

Cancer Microenvironment

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Neutral endopeptidase inhibits prostate cancer cell migration by blocking focal adhesion kinase signaling

Cited by 137 publications

References 45 publications

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

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

Toward an Integrative Analysis of the Tumor Microenvironment in Ovarian Epithelial Carcinoma

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