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. 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.
Galan-Moya
Eva M
EM
CRIB/Facultad de medicina, UCLM, 02006 Albacete, Spain.
Hernandez-Losa
Javier
J
Aceves Luquero
Clara I
CI
de la Cruz-Morcillo
Miguel A
MA
Ramírez-Castillejo
Carmen
C
Callejas-Valera
Juan L
JL
Arriaga
Angel
A
Aranburo
Antonio Fernandez
AF
Ramón y Cajal
Santiago
S
Silvio Gutkind
J
J
Sánchez-Prieto
Ricardo
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010879:Piperazines / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011500:Protein Synthesis Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003513:Cycloheximide; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D002945:Cisplatin