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PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases
Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpress...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227704/ https://www.ncbi.nlm.nih.gov/pubmed/25386922 http://dx.doi.org/10.1371/journal.pone.0112148 |
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author | Martín-Sánchez, Esperanza Odqvist, Lina Rodríguez-Pinilla, Socorro M. Sánchez-Beato, Margarita Roncador, Giovanna Domínguez-González, Beatriz Blanco-Aparicio, Carmen García Collazo, Ana M. Cantalapiedra, Esther González Fernández, Joaquín Pastor del Olmo, Soraya Curiel Pisonero, Helena Madureira, Rebeca Almaraz, Carmen Mollejo, Manuela Alves, F. Javier Menárguez, Javier González-Palacios, Fernando Rodríguez-Peralto, José Luis Ortiz-Romero, Pablo L. Real, Francisco X. García, Juan F. Bischoff, James R. Piris, Miguel A. |
author_facet | Martín-Sánchez, Esperanza Odqvist, Lina Rodríguez-Pinilla, Socorro M. Sánchez-Beato, Margarita Roncador, Giovanna Domínguez-González, Beatriz Blanco-Aparicio, Carmen García Collazo, Ana M. Cantalapiedra, Esther González Fernández, Joaquín Pastor del Olmo, Soraya Curiel Pisonero, Helena Madureira, Rebeca Almaraz, Carmen Mollejo, Manuela Alves, F. Javier Menárguez, Javier González-Palacios, Fernando Rodríguez-Peralto, José Luis Ortiz-Romero, Pablo L. Real, Francisco X. García, Juan F. Bischoff, James R. Piris, Miguel A. |
author_sort | Martín-Sánchez, Esperanza |
collection | PubMed |
description | Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL. |
format | Online Article Text |
id | pubmed-4227704 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-42277042014-11-18 PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases Martín-Sánchez, Esperanza Odqvist, Lina Rodríguez-Pinilla, Socorro M. Sánchez-Beato, Margarita Roncador, Giovanna Domínguez-González, Beatriz Blanco-Aparicio, Carmen García Collazo, Ana M. Cantalapiedra, Esther González Fernández, Joaquín Pastor del Olmo, Soraya Curiel Pisonero, Helena Madureira, Rebeca Almaraz, Carmen Mollejo, Manuela Alves, F. Javier Menárguez, Javier González-Palacios, Fernando Rodríguez-Peralto, José Luis Ortiz-Romero, Pablo L. Real, Francisco X. García, Juan F. Bischoff, James R. Piris, Miguel A. PLoS One Research Article Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL. Public Library of Science 2014-11-11 /pmc/articles/PMC4227704/ /pubmed/25386922 http://dx.doi.org/10.1371/journal.pone.0112148 Text en © 2014 Martín-Sánchez 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 Martín-Sánchez, Esperanza Odqvist, Lina Rodríguez-Pinilla, Socorro M. Sánchez-Beato, Margarita Roncador, Giovanna Domínguez-González, Beatriz Blanco-Aparicio, Carmen García Collazo, Ana M. Cantalapiedra, Esther González Fernández, Joaquín Pastor del Olmo, Soraya Curiel Pisonero, Helena Madureira, Rebeca Almaraz, Carmen Mollejo, Manuela Alves, F. Javier Menárguez, Javier González-Palacios, Fernando Rodríguez-Peralto, José Luis Ortiz-Romero, Pablo L. Real, Francisco X. García, Juan F. Bischoff, James R. Piris, Miguel A. PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases |
title | PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases |
title_full | PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases |
title_fullStr | PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases |
title_full_unstemmed | PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases |
title_short | PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases |
title_sort | pim kinases as potential therapeutic targets in a subset of peripheral t cell lymphoma cases |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227704/ https://www.ncbi.nlm.nih.gov/pubmed/25386922 http://dx.doi.org/10.1371/journal.pone.0112148 |
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