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Molecular and Cellular Biology, August 2007, p. 5499-5513, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.01080-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress ^,

Departments of Medicine, Biochemistry, and Pharmacology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298

Received 15 June 2006/ Returned for modification 29 September 2006/ Accepted 17 May 2007

Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells. Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1/2-ERK1/2 signaling-independent mechanism and that this phenomenon plays a key functional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from sorafenib-mediated lethality, indicating that sorafenib-induced cell death is unrelated to MEK1/2-ERK1/2 pathway inactivation. Notably, treatment with sorafenib induced endoplasmic reticulum (ER) stress in human leukemia cells (U937) manifested by immediate cytosolic-calcium mobilization, GADD153 and GADD34 protein induction, PKR-like ER kinase (PERK) and eukaryotic initiation factor 2 (eIF2) phosphorylation, XBP1 splicing, and a general reduction in protein synthesis as assessed by [³⁵S]methionine incorporation. These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic-calcium mobilization and a significant decline in GRP78/Bip protein levels. Interestingly, enforced expression of IRE1 markedly reduced sorafenib-mediated apoptosis, whereas knockdown of IRE1 or XBP1, disruption of PERK activity, or inhibition of eIF2 phosphorylation enhanced sorafenib-mediated lethality. Finally, downregulation of caspase-2 or caspase-4 by small interfering RNA significantly diminished apoptosis induced by sorafenib. Together, these findings demonstrate that ER stress represents a central component of a MEK1/2-ERK1/2-independent cell death program triggered by sorafenib.

Published ahead of print on 4 June 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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