Involvement of a Rho-ROCK-JNK pathway in arsenic trioxide-induced apoptosis in chronic myelogenous leukemia cells.
The apoptotic signals activated by As(2)O(3) in the chronic myelogenous leukemia (CML) cell lines K562 and KCL22 were investigated. As(2)O(3) was found to induce apoptosis in these cells via the intrinsic pathway. As(2)O(3) also induced a sustained c-Jun NH2-terminal kinase (JNK) activation which preceded and was necessary for caspase-9 activation. We established that Rho and its effector, the kinase ROCK, are activated by As(2)O(3). Inhibition of either Rho or ROCK prevented JNK activation and protected against apoptosis. Thus, in CML cells, apoptosis induced by As(2)O(3) is mediated, at least in part, via a Rho-ROCK-JNK axis. These findings define a novel signaling pathway for As(2)O(3)-induced apoptosis.
Potin
Sophie
S
Inserm U749, Faculté de Pharmacie, 5 rue JB Clément, 92290 Châtenay-Malabry, France.
Bertoglio
Jacques
J
Bréard
Jacqueline
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053453:Caspase 9 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D000970:Antineoplastic Agents; D001152:Arsenicals; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D010087:Oxides; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053453:Caspase 9; D020741:rho GTP-Binding Proteins; D000077237:Arsenic Trioxide