c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy

Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin....

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Veröffentlicht in:International journal of cancer 2008-01, Vol.122 (2), p.289-297
Hauptverfasser: Galan‐Moya, Eva M., Hernandez‐Losa, Javier, Aceves Luquero, Clara I., de la Cruz‐Morcillo, Miguel A., Ramírez‐Castillejo, Carmen, Callejas‐Valera, Juan L., Arriaga, Angel, Aranburo, Antonio Fernandez, Cajal, Santiago Ramón y, Silvio Gutkind, J., Sánchez‐Prieto, Ricardo
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container_end_page 297
container_issue 2
container_start_page 289
container_title International journal of cancer
container_volume 122
creator Galan‐Moya, Eva M.
Hernandez‐Losa, Javier
Aceves Luquero, Clara I.
de la Cruz‐Morcillo, Miguel A.
Ramírez‐Castillejo, Carmen
Callejas‐Valera, Juan L.
Arriaga, Angel
Aranburo, Antonio Fernandez
Cajal, Santiago Ramón y
Silvio Gutkind, J.
Sánchez‐Prieto, Ricardo
description Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c‐Abl. Indeed, c‐Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c‐Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia‐derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c‐Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c‐Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act. © 2007 Wiley‐Liss, Inc.
doi_str_mv 10.1002/ijc.23063
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In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c‐Abl. Indeed, c‐Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c‐Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia‐derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c‐Abl overexpression on p38 MAPK activation. 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source MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
subjects Antineoplastic agents
Antineoplastic Agents - pharmacology
Benzamides
Biological and medical sciences
Cell Line, Tumor
cisplatin
Cisplatin - pharmacology
Cycloheximide - pharmacology
c‐Abl
Gene Expression Regulation, Leukemic
Gene Expression Regulation, Neoplastic
General aspects
Humans
Imatinib Mesylate
MAP Kinase Kinase 6 - metabolism
MAP Kinase Signaling System
Medical sciences
MKK6
Models, Biological
p38 MAPK
p38 Mitogen-Activated Protein Kinases - metabolism
Pharmacology. Drug treatments
Piperazines - pharmacology
Protein Synthesis Inhibitors - pharmacology
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins c-abl - metabolism
Pyrimidines - pharmacology
Tumors
title c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy
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