Endothelin-Converting Enzyme-1 Inhibition and Growth of Human Glioblastoma Cells

Berger, Yann; Dehmlow, Henrietta; Blum‐Kaelin, Denise; Kitas, Eric; Löffler, Bernd–Michael; Aebi, Johannes D.; Juillerat‐Jeanneret, Lucienne

doi:10.1021/jm040857x

Cited by 30 publications

(28 citation statements)

References 46 publications

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“…A separate study has also reported that ECE-specific inhibitors may represent a novel therapeutic approach to human cancers. 54 Our study is the first to implicate that ECE-1 siRNA can effectively downregulate ECE-1 expression in oral SCC cells. Recent studies have demonstrated that siRNA targeting cell proliferation genes and antiapoptosis genes could provide novel therapies for cancer.…”

Section: Discussionmentioning

confidence: 65%

Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

Awano

Dawson

Hunter

et al. 2005

Intl Journal of Cancer

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The present study focused on the endothelin axis in human oral squamous cell carcinoma (SCC) cells. We investigated the expression and distribution of endothelin-1 (ET-1), its receptors (endothelin-A receptor (ET A R) and endothelin-B receptor (ET B R)) and isoforms of its specific converting enzyme 1b, 1c) and the report on their relative influences on cell proliferation. We also investigated the effect of an ECE-specific inhibitor (ECE-i) and siRNA targeting of the ECE-1 gene on SCC cell proliferation. We observed the expression of ET-1, ET A R, ET B R and all endothelin-converting enzyme-1 (ECE-1) isoforms in oral SCC cells, but only the expression of ET-1, ET B R and ECE-1 was increased when compared to normal human epidermal keratinocytes. ET-1 alone stimulated proliferation of oral SCC cells. Antagonists of either ET A R or ET B R inhibited ET-1-mediated proliferation. Decreased ECE-1 expression after ECE siRNA treatment reduced SCC cell proliferation. Antiproliferative effects were also observed by inhibiting ECE activity with ECE-i. In conclusion, the present study demonstrates that modulation of the endothelin system in oral SCC cells might provide a novel therapeutic protocol for oral cancer. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 65%

Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

Awano

Dawson

Hunter

et al. 2005

Intl Journal of Cancer

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“…Addition of exogenous ET-1 only partially recovered this effect on invasion implicating an alternative role for ECE-1 independent of ET-1 generation. A unique role for ECE-1 has also been proposed by Berger et al (2005) who demonstrated that ECE-1 inhibitors could inhibit proliferation of human glioblastoma cells without reducing ET-1 levels (Berger et al, 2005). Endothelin-converting enzyme 1a and ECE-1c isoforms were next transiently expressed in epithelial (PC-3) and stromal (STO) cells to assess their influence on invasion.…”

Section: Discussionmentioning

confidence: 98%

Isoforms of endothelin-converting enzyme-1 (ECE-1) have opposing effects on prostate cancer cell invasion

et al. 2008

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Cross-talk between tumour and stromal cells can profoundly influence cancer cell invasion by increasing the availability of mitogenic peptides such as endothelin-1 (ET-1). Endothelin-1 is elevated in men with metastatic prostate cancer (PC), and can exert both an autocrine (epithelial) and a paracrine (stromal) influence on growth. Endothelin-1 is generated from its inactive precursor big-ET-1 by endothelin-converting enzyme 1 (ECE-1). We and others have demonstrated that ECE-1 expression is significantly elevated in tumours and surrounding stromal tissue. Our current data show siRNA-mediated knockdown of stromal ECE-1 reduces epithelial (PC-3) cell invasion in coculture. Interestingly, readdition of ET-1 only partially recovers this effect suggesting a novel role for ECE-1 independent of ET-1 activation. Parallel knockdown of ECE-1 in both stromal and epithelial compartments results in an additive decrease in cell invasion. We extrapolated this observation to the four recognised isoforms ECE-1a, ECE-1b, ECE-1c and ECE-1d. Only ECE-1a and ECE-1c were significant but with reciprocal effects on cell invasion. Transient ECE-1c overexpression increased PC-3 invasiveness through matrigel, whereas transient ECE-1a expression suppressed invasion. Furthermore, transient ECE-1a expression in stromal cells strongly counteracts the effect of transient ECE-1c expression in PC-3 cells. The ECE-1 isoforms may, therefore, be relevant targets for antiinvasive therapy in prostate and other cancers.

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“…This resulted into reduced autocrine actions of ET-1 and consequently to a decrease in SCC cell proliferation [32]. Berger et al who originally reported elevated levels of ECE-1 in human glioblastomas, recently also proved a growthinhibitory effect of non-peptide ECE-1 inhibitors in glioblastoma cells [24]. To determine the potential clinical relevance of targeting ECE-1 in breast cancer, we investigated the effects of the non-peptide selective ECE-1 inhibitor RO 67-7447 on ET-1 expression in MCF-7 breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…For all in vitro experiments, non-peptide selective ECE-1 inhibitor RO 67-7447 ((2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester) [24] was dissolved in methanol and diluted to the particular concentration. The compound was kindly provided by F. Hoffmann-La Roche (Basel, Switzerland).…”

Section: Inhibition Of Ece-1mentioning

confidence: 99%

On the role of endothelin-converting enzyme-1 (ECE-1) and neprilysin in human breast cancer

Smollich

Götte

Yip

et al. 2007

Breast Cancer Res Treat

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Endothelin-1 (ET-1) and its receptors, ET(A)R and ET(B)R, are overexpressed in breast carcinomas. However, little is known about the relevance of endothelin-converting enzyme-1 (ECE-1) and ET-1 degrading neprilysin (NEP). In this study, expression of ECE-1 and NEP was determined in 600 breast cancer tissue samples by immunohistochemistry; staining results were correlated with clinicopathological parameters. For ECE-1 expression, we found a significant correlation with VEGF (P < 0.001) and ET(A)R expression (P = 0.048). While patients with ECE-1 overexpressing tumours had more frequent disease recurrence (P = 0.03), NEP overexpression correlated with improved disease-free survival (DFS) (P = 0.023) and less frequent metastasis (P = 0.046). Also, a decrease of NEP expression with malignant progression (G1-G3) was found. ECE-1 inhibition using the selective ECE-1 inhibitor RO 67-7447 in MCF-7 breast cancer cells led to a significantly decreased ET-1 expression and reduced cell invasiveness (54.3% of controls, P = 0.014). Our results indicate that overexpression of ECE-1 is associated with unfavourable outcome, whereas NEP positively influences survival. Thus, expression of ECE-1 and NEP may have prognostic relevance. Due to the anti-invasive effect of the selective ECE-1 inhibitor, targeting ECE-1 may represent an innovative option in future breast cancer therapy.

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Endothelin-Converting Enzyme-1 Inhibition and Growth of Human Glioblastoma Cells

Cited by 30 publications

References 46 publications

Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE‐1 blocks cell proliferation

Isoforms of endothelin-converting enzyme-1 (ECE-1) have opposing effects on prostate cancer cell invasion

On the role of endothelin-converting enzyme-1 (ECE-1) and neprilysin in human breast cancer

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