Involvement of a Rho-ROCK-JNK pathway in arsenic trioxide-induced apoptosis in chronic myelogenous leukemia cells

The apoptotic signals activated by As2O3 in the chronic myelogenous leukemia (CML) cell lines K562 and KCL22 were investigated. As2O3 was found to induce apoptosis in these cells via the intrinsic pathway. As2O3 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 As2O3. Inhibition of either Rho or ROCK prevented JNK activation and protected against apoptosis. Thus, in CML cells, apoptosis induced by As2O3 is mediated, at least in part, via a Rho-ROCK-JNK axis. These findings define a novel signaling pathway for As2O3-induced apoptosis.