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Vol. 16, Issue 8, 3821-3831, August 2005

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Doxorubicin Requires the Sequential Activation of Caspase-2, Protein Kinase C, and c-Jun NH₂-terminal Kinase to Induce Apoptosis

Theocharis Panaretakis ^*, Edward Laane ^*, Katja Pokrovskaja ^*, Ann-Charlotte Björklund ^*, Aristidis Moustakas , Boris Zhivotovsky , Mats Heyman , Maria C. Shoshan ^*, and Dan Grandér ^*

^* Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden; Ludwig Institute for Cancer Research, Biomedical Center, S-752 37 Uppsala, Sweden; Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute, S-171 77 Stockholm, Sweden; and Childhood Cancer Research Unit, Astrid Lindgrens Children's Hospital, Karolinska Hospital, SE-171 76 Stockholm, Sweden

Submitted October 4, 2004; Revised May 11, 2005; Accepted May 18, 2005
Monitoring Editor: John Cleveland

Here, we identified caspase-2, protein kinase C (PKC), and c-Jun NH₂-terminal kinase (JNK) as key components of the doxorubicin-induced apoptotic cascade. Using cells stably transfected with an antisense construct for caspase-2 (AS2) as well as a chemical caspase-2 inhibitor, we demonstrate that caspase-2 is required in doxorubicin-induced apoptosis. We also identified PKC as a novel caspase-2 substrate. PKC was cleaved/activated in a caspase-2–dependent manner after doxorubicin treatment both in cells and in vitro. PKC is furthermore required for efficient doxorubicin-induced apoptosis because its chemical inhibition as well as adenoviral expression of a kinase dead (KD) mutant of PKC severely attenuated doxorubicin-induced apoptosis. Furthermore, PKC and JNK inhibition show that PKC lies upstream of JNK in doxorubicin-induced death. Jnk-deficient mouse embryo fibroblasts (MEFs) were highly resistant to doxorubicin compared with wild type (WT), as were WT Jurkat cells treated with SP600125, further supporting the importance of JNK in doxorubicin-induced apoptosis. Chemical inhibitors for PKC and JNK do not synergize and do not function in doxorubicin-treated AS2 cells. Caspase-2, PKC, and JNK were furthermore implicated in doxorubicin-induced apoptosis of primary acute lymphoblastic leukemia blasts. The data thus support a sequential model involving caspase-2, PKC, and JNK signaling in response to doxorubicin, leading to the activation of Bak and execution of apoptosis.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Dan Grandér (Dan.Grander{at}cck.ki.se).

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