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Alpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1

Melanoma is the most dangerous type of skin cancer accounting for 48,000 deaths worldwide each year and an average survival rate of about 6-10 months with conventional treatment. Tumor metastasis and chemoresistance of melanoma cells are reported as the main reasons for the insufficiency of currentl...

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Autores principales: Kreiseder, Birgit, Holper-Schichl, Yvonne M, Muellauer, Barbara, Jacobi, Nico, Pretsch, Alexander, Schmid, Johannes A., de Martin, Rainer, Hundsberger, Harald, Eger, Andreas, Wiesner, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368766/
https://www.ncbi.nlm.nih.gov/pubmed/25793618
http://dx.doi.org/10.1371/journal.pone.0119402
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author Kreiseder, Birgit
Holper-Schichl, Yvonne M
Muellauer, Barbara
Jacobi, Nico
Pretsch, Alexander
Schmid, Johannes A.
de Martin, Rainer
Hundsberger, Harald
Eger, Andreas
Wiesner, Christoph
author_facet Kreiseder, Birgit
Holper-Schichl, Yvonne M
Muellauer, Barbara
Jacobi, Nico
Pretsch, Alexander
Schmid, Johannes A.
de Martin, Rainer
Hundsberger, Harald
Eger, Andreas
Wiesner, Christoph
author_sort Kreiseder, Birgit
collection PubMed
description Melanoma is the most dangerous type of skin cancer accounting for 48,000 deaths worldwide each year and an average survival rate of about 6-10 months with conventional treatment. Tumor metastasis and chemoresistance of melanoma cells are reported as the main reasons for the insufficiency of currently available treatments for late stage melanoma. The cytoskeletal linker protein α-catulin (CTNNAL1) has been shown to be important in inflammation, apoptosis and cytoskeletal reorganization. Recently, we found an elevated expression of α-catulin in melanoma cells. Ectopic expression of α-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. In the current study we showed that α-catulin knockdown reduced NF-κB and AP-1 activity in malignant melanoma cells. Further, downregulation of α-catulin diminished ERK phosphorylation in malignant melanoma cells and sensitized them to treatment with chemotherapeutic drugs. In particular, cisplatin treatment led to decreased ERK-, JNK- and c-Jun phosphorylation in α-catulin knockdown melanoma cells, which was accompanied by enhanced apoptosis compared to control cells. Altogether, these results suggest that targeted inhibition of α-catulin may be used as a viable therapeutic strategy to chemosensitize melanoma cells to cisplatin by down-regulation of NF-κB and MAPK pathways.
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spelling pubmed-43687662015-03-27 Alpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1 Kreiseder, Birgit Holper-Schichl, Yvonne M Muellauer, Barbara Jacobi, Nico Pretsch, Alexander Schmid, Johannes A. de Martin, Rainer Hundsberger, Harald Eger, Andreas Wiesner, Christoph PLoS One Research Article Melanoma is the most dangerous type of skin cancer accounting for 48,000 deaths worldwide each year and an average survival rate of about 6-10 months with conventional treatment. Tumor metastasis and chemoresistance of melanoma cells are reported as the main reasons for the insufficiency of currently available treatments for late stage melanoma. The cytoskeletal linker protein α-catulin (CTNNAL1) has been shown to be important in inflammation, apoptosis and cytoskeletal reorganization. Recently, we found an elevated expression of α-catulin in melanoma cells. Ectopic expression of α-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. In the current study we showed that α-catulin knockdown reduced NF-κB and AP-1 activity in malignant melanoma cells. Further, downregulation of α-catulin diminished ERK phosphorylation in malignant melanoma cells and sensitized them to treatment with chemotherapeutic drugs. In particular, cisplatin treatment led to decreased ERK-, JNK- and c-Jun phosphorylation in α-catulin knockdown melanoma cells, which was accompanied by enhanced apoptosis compared to control cells. Altogether, these results suggest that targeted inhibition of α-catulin may be used as a viable therapeutic strategy to chemosensitize melanoma cells to cisplatin by down-regulation of NF-κB and MAPK pathways. Public Library of Science 2015-03-20 /pmc/articles/PMC4368766/ /pubmed/25793618 http://dx.doi.org/10.1371/journal.pone.0119402 Text en © 2015 Kreiseder 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kreiseder, Birgit
Holper-Schichl, Yvonne M
Muellauer, Barbara
Jacobi, Nico
Pretsch, Alexander
Schmid, Johannes A.
de Martin, Rainer
Hundsberger, Harald
Eger, Andreas
Wiesner, Christoph
Alpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1
title Alpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1
title_full Alpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1
title_fullStr Alpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1
title_full_unstemmed Alpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1
title_short Alpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1
title_sort alpha-catulin contributes to drug-resistance of melanoma by activating nf-κb and ap-1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368766/
https://www.ncbi.nlm.nih.gov/pubmed/25793618
http://dx.doi.org/10.1371/journal.pone.0119402
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