A prokaryotic S1P lyase degrades extracellular S1P in vitro and in vivo: implication for treating hyperproliferative disorders

Huwiler, Andrea; Bourquin, Florence; Kotelevets, Nataliya; Pastukhov, Oleksandr; Capitani, Guido; Grütter, Markus G; Zangemeister-Wittke, Uwe (2011). A prokaryotic S1P lyase degrades extracellular S1P in vitro and in vivo: implication for treating hyperproliferative disorders. PLoS ONE, 6(8), e22436. Lawrence, Kans.: Public Library of Science 10.1371/journal.pone.0022436

[img]
Preview
Text
journal.pone.0022436.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (824kB) | Preview

Sphingosine-1-phosphate (S1P) regulates a broad spectrum of fundamental cellular processes like proliferation, death, migration and cytokine production. Therefore, elevated levels of S1P may be causal to various pathologic conditions including cancer, fibrosis, inflammation, autoimmune diseases and aberrant angiogenesis. Here we report that S1P lyase from the prokaryote Symbiobacterium thermophilum (StSPL) degrades extracellular S1P in vitro and in blood. Moreover, we investigated its effect on cellular responses typical of fibrosis, cancer and aberrant angiogenesis using renal mesangial cells, endothelial cells, breast (MCF-7) and colon (HCT 116) carcinoma cells as disease models. In all cell types, wild-type StSPL, but not an inactive mutant, disrupted MAPK phosphorylation stimulated by exogenous S1P. Functionally, disruption of S1P receptor signaling by S1P depletion inhibited proliferation and expression of connective tissue growth factor in mesangial cells, proliferation, migration and VEGF expression in carcinoma cells, and proliferation and migration of endothelial cells. Upon intravenous injection of StSPL in mice, plasma S1P levels rapidly declined by 70% within 1 h and then recovered to normal 6 h after injection. Using the chicken chorioallantoic membrane model we further demonstrate that also under in vivo conditions StSPL, but not the inactive mutant, inhibited tumor cell-induced angiogenesis as an S1P-dependent process. Our data demonstrate that recombinant StSPL is active under extracellular conditions and holds promise as a new enzyme therapeutic for diseases associated with increased levels of S1P and S1P receptor signaling.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea; Kotelevets, Nataliya; Pastukhov, Oleksandr and Zangemeister-Wittke, Uwe

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1932-6203

Publisher:

Public Library of Science

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:18

Last Modified:

18 Feb 2016 14:27

Publisher DOI:

10.1371/journal.pone.0022436

PubMed ID:

21829623

Web of Science ID:

000293511200009

BORIS DOI:

10.7892/boris.5458

URI:

https://boris.unibe.ch/id/eprint/5458 (FactScience: 210205)

Actions (login required)

Edit item Edit item
Provide Feedback