期刊
CELL CYCLE
卷 10, 期 23, 页码 4138-4148出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.23.18323
关键词
Foretinib; mitotic catastrophe; apoptosis; caspase 2; Plk1
类别
资金
- INCA [PL06-026]
- Ligue Nationale Contre le Cancer
- Fondation De France
Mitotic catastrophe (MC) is induced when stressed cells enter prematurely or inappropriately into mitosis and can be caused by ionizing radiation and anticancer drugs. Foretinib is a multikinase inhibitor whose mechanism of action is incompletely understood. We investigated here the effect of Foretinib on chronic myelogenous leukemia (CML) cell lines either sensitive (IM-S) or resistant (IM-R) to the tyrosine kinase inhibitor Imatinib. Foretinib decreased viability and clonogenic potential of IM-S and IM-R CML cells as well. Foretinib-treated cells exhibited increased size, spindle assembly checkpoint anomalies and enhanced ploidy that collectively evoked mitotic catastrophe (MC). Accordingly, Foretinib-stimulated CML cells displayed decreased expression of Cdk1, cyclin B1 and Plk1. In addition, Foretinib triggered caspase 2 activation that precedes mitochondrial membrane permeabilization. Accordingly, z-VAD-fmk and a caspase 2 siRNA abolished Foretinib-mediated cell death but failed to affect MC, indicating that Foretinib-mediated apoptosis and MC are two independent events. Anisomycin, a JNK activator, impaired Foretinib-induced MC and inhibition or knockdown of JNK phenotyped its effect on MC. Moreover, we found that Foretinib acted as a potent inhibitor of JNK. Importantly, Foretinib exhibited no or very little effect on normal peripheral blood mononuclear cells, monocytes or melanocytes cells but efficiently inhibited the clonogenic potential of CD34(+) cell from CML patients. Collectively, our data show that the multikinase inhibitor Foretinib induces MC in CML cells and other cell lines via JNK-dependent inhibition of Plk1 expression and triggered apoptosis by a caspase 2-mediated mechanism. This unusual mechanism of action may have important implications for the treatment of cancer.
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