Cargando…
The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen
The vacuolar-type H(+)-ATPase (v-ATPase) is the major proton pump that acidifies intracellular compartments of eukaryotic cells. Since the inhibition of v-ATPase resulted in anti-tumor and anti-metastatic effects in different tumor models, this enzyme has emerged as promising strategy against cancer...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133348/ https://www.ncbi.nlm.nih.gov/pubmed/30204757 http://dx.doi.org/10.1371/journal.pone.0203053 |
_version_ | 1783354491021557760 |
---|---|
author | Luong, Betty Schwenk, Rebecca Bräutigam, Jacqueline Müller, Rolf Menche, Dirk Bischoff, Iris Fürst, Robert |
author_facet | Luong, Betty Schwenk, Rebecca Bräutigam, Jacqueline Müller, Rolf Menche, Dirk Bischoff, Iris Fürst, Robert |
author_sort | Luong, Betty |
collection | PubMed |
description | The vacuolar-type H(+)-ATPase (v-ATPase) is the major proton pump that acidifies intracellular compartments of eukaryotic cells. Since the inhibition of v-ATPase resulted in anti-tumor and anti-metastatic effects in different tumor models, this enzyme has emerged as promising strategy against cancer. Here, we used the well-established v-ATPase inhibitor archazolid, a natural product first isolated from the myxobacterium Archangium gephyra, to study the consequences of v-ATPase inhibition in endothelial cells (ECs), in particular on the interaction between ECs and cancer cells, which has been neglected so far. Human endothelial cells treated with archazolid showed an increased adhesion of tumor cells, whereas the transendothelial migration of tumor cells was reduced. The adhesion process was independent from the EC adhesion molecules ICAM-1, VCAM-1, E-selectin and N-cadherin. Instead, the adhesion was mediated by β1-integrins expressed on tumor cells, as blocking of the integrin β1 subunit reversed this process. Tumor cells preferentially adhered to the β1-integrin ligand collagen and archazolid led to an increase in the amount of collagen on the surface of ECs. The accumulation of collagen was accompanied by a strong decrease of the expression and activity of the protease cathepsin B. Overexpression of cathepsin B in ECs prevented the capability of archazolid to increase the adhesion of tumor cells onto ECs. Our study demonstrates that the inhibition of v-ATPase by archazolid induces a pro-adhesive phenotype in endothelial cells that promotes their interaction with cancer cells, whereas the transmigration of tumor cells was reduced. These findings further support archazolid as a promising anti-metastatic compound. |
format | Online Article Text |
id | pubmed-6133348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61333482018-09-27 The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen Luong, Betty Schwenk, Rebecca Bräutigam, Jacqueline Müller, Rolf Menche, Dirk Bischoff, Iris Fürst, Robert PLoS One Research Article The vacuolar-type H(+)-ATPase (v-ATPase) is the major proton pump that acidifies intracellular compartments of eukaryotic cells. Since the inhibition of v-ATPase resulted in anti-tumor and anti-metastatic effects in different tumor models, this enzyme has emerged as promising strategy against cancer. Here, we used the well-established v-ATPase inhibitor archazolid, a natural product first isolated from the myxobacterium Archangium gephyra, to study the consequences of v-ATPase inhibition in endothelial cells (ECs), in particular on the interaction between ECs and cancer cells, which has been neglected so far. Human endothelial cells treated with archazolid showed an increased adhesion of tumor cells, whereas the transendothelial migration of tumor cells was reduced. The adhesion process was independent from the EC adhesion molecules ICAM-1, VCAM-1, E-selectin and N-cadherin. Instead, the adhesion was mediated by β1-integrins expressed on tumor cells, as blocking of the integrin β1 subunit reversed this process. Tumor cells preferentially adhered to the β1-integrin ligand collagen and archazolid led to an increase in the amount of collagen on the surface of ECs. The accumulation of collagen was accompanied by a strong decrease of the expression and activity of the protease cathepsin B. Overexpression of cathepsin B in ECs prevented the capability of archazolid to increase the adhesion of tumor cells onto ECs. Our study demonstrates that the inhibition of v-ATPase by archazolid induces a pro-adhesive phenotype in endothelial cells that promotes their interaction with cancer cells, whereas the transmigration of tumor cells was reduced. These findings further support archazolid as a promising anti-metastatic compound. Public Library of Science 2018-09-11 /pmc/articles/PMC6133348/ /pubmed/30204757 http://dx.doi.org/10.1371/journal.pone.0203053 Text en © 2018 Luong et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Luong, Betty Schwenk, Rebecca Bräutigam, Jacqueline Müller, Rolf Menche, Dirk Bischoff, Iris Fürst, Robert The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen |
title | The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen |
title_full | The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen |
title_fullStr | The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen |
title_full_unstemmed | The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen |
title_short | The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen |
title_sort | vacuolar-type atpase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133348/ https://www.ncbi.nlm.nih.gov/pubmed/30204757 http://dx.doi.org/10.1371/journal.pone.0203053 |
work_keys_str_mv | AT luongbetty thevacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT schwenkrebecca thevacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT brautigamjacqueline thevacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT mullerrolf thevacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT menchedirk thevacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT bischoffiris thevacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT furstrobert thevacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT luongbetty vacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT schwenkrebecca vacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT brautigamjacqueline vacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT mullerrolf vacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT menchedirk vacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT bischoffiris vacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen AT furstrobert vacuolartypeatpaseinhibitorarchazolidincreasestumorcelladhesiontoendothelialcellsbyaccumulatingextracellularcollagen |