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DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions

DLC1 (Deleted in Liver Cancer 1) gene encodes a RhoGTPase-activating protein (RhoGAP), which exerts most of its tumor suppressor functions through suppression of small Rho GTPases proteins RhoA, RhoB, RhoC and to some degree Cdc42, but not Rac. RhoGTPases are implicated in NF-κB activation in highly...

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Autores principales: Tripathi, Veenu, Popescu, Nicholas C, Zimonjic, Drazen B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967735/
https://www.ncbi.nlm.nih.gov/pubmed/24683532
http://dx.doi.org/10.1186/2193-1801-3-27
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author Tripathi, Veenu
Popescu, Nicholas C
Zimonjic, Drazen B
author_facet Tripathi, Veenu
Popescu, Nicholas C
Zimonjic, Drazen B
author_sort Tripathi, Veenu
collection PubMed
description DLC1 (Deleted in Liver Cancer 1) gene encodes a RhoGTPase-activating protein (RhoGAP), which exerts most of its tumor suppressor functions through suppression of small Rho GTPases proteins RhoA, RhoB, RhoC and to some degree Cdc42, but not Rac. RhoGTPases are implicated in NF-κB activation in highly invasive prostate carcinoma (PCA), with consequences on cell proliferation, survival and metastatic capacity. Here we demonstrate that DLC1 transduction in two androgen-independent (AI) and highly metastatic PCA cell lines negatively regulates NF-κB activity in a GAP- and α-catenin-dependent manner. Expressed DLC1 protein suppresses the phosphorylation of NF-κB inhibitor, IκBα, causes its relocation from membrane ruffles into cytoplasm and attenuates its ubiquitination and subsequent degradation. DLC1-mediated NF-kB suppression and its effects are comparable to NF-κB inhibition using either shRNA knockdown or peptide inhibitor. Expression of transduced DLC1 suppressed the expression of NF-κB mediated genes. Such effects were found to be reliant on presence of calcium, indicating that the observed modifications are dependent on, and enabled by DLC-mediated stabilization of adherens junctions. These results expand the multitude of DLC1 interactions with other genes that modulate its oncosuppressive function, and may have potential therapeutic implications.
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spelling pubmed-39677352014-03-28 DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions Tripathi, Veenu Popescu, Nicholas C Zimonjic, Drazen B Springerplus Research DLC1 (Deleted in Liver Cancer 1) gene encodes a RhoGTPase-activating protein (RhoGAP), which exerts most of its tumor suppressor functions through suppression of small Rho GTPases proteins RhoA, RhoB, RhoC and to some degree Cdc42, but not Rac. RhoGTPases are implicated in NF-κB activation in highly invasive prostate carcinoma (PCA), with consequences on cell proliferation, survival and metastatic capacity. Here we demonstrate that DLC1 transduction in two androgen-independent (AI) and highly metastatic PCA cell lines negatively regulates NF-κB activity in a GAP- and α-catenin-dependent manner. Expressed DLC1 protein suppresses the phosphorylation of NF-κB inhibitor, IκBα, causes its relocation from membrane ruffles into cytoplasm and attenuates its ubiquitination and subsequent degradation. DLC1-mediated NF-kB suppression and its effects are comparable to NF-κB inhibition using either shRNA knockdown or peptide inhibitor. Expression of transduced DLC1 suppressed the expression of NF-κB mediated genes. Such effects were found to be reliant on presence of calcium, indicating that the observed modifications are dependent on, and enabled by DLC-mediated stabilization of adherens junctions. These results expand the multitude of DLC1 interactions with other genes that modulate its oncosuppressive function, and may have potential therapeutic implications. Springer International Publishing 2014-01-14 /pmc/articles/PMC3967735/ /pubmed/24683532 http://dx.doi.org/10.1186/2193-1801-3-27 Text en © Tripathi et al.; licensee Springer. 2014 This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Tripathi, Veenu
Popescu, Nicholas C
Zimonjic, Drazen B
DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions
title DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions
title_full DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions
title_fullStr DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions
title_full_unstemmed DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions
title_short DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions
title_sort dlc1 suppresses nf-κb activity in prostate cancer cells due to its stabilizing effect on adherens junctions
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967735/
https://www.ncbi.nlm.nih.gov/pubmed/24683532
http://dx.doi.org/10.1186/2193-1801-3-27
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